Microglia and Mast Cells in Neuro-COVID: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Kempuraj Duraisamy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). About 45% of COVID-19 patients experience several symptoms a few months after the initial infection and develop post-acute sequelae of SARS-CoV-2 (PASC), referred to as “Long-COVID,” characterized by persistent physical and mental fatigue. However, the exact pathogenetic mechanisms affecting the brain are still not well-understood. There is increasing evidence of neurovascular inflammation in the brain.

  • ACE2
  • brain
  • coronavirus
  • cytokines
  • inflammation

1. Microglia-Induced Neuroinflammation and Mental Health

Microglia are specialized macrophage-like immune cells of the CNS and constitute about 7 percent of non-neuronal cells in the brain [121][1]. It has been reported that one microglial cell serves 1 to 100 neuronal cells in various brain areas with different neuronal densities [121][1]. Microglia are important for CNS homeostasis both in health and disease states [122][2], especially neurodegenerative [123,124,125,126,127,128,129][3][4][5][6][7][8][9] and neuroinflammatory [122,128,130,131][2][8][10][11] diseases, including COVID-19 [83,132][12][13]. During neuroinflammatory response and brain homeostasis maintenance, microglia can change their numbers, morphological characteristics, molecular pattern, and functions [132][13]. Activated microglia release pro-inflammatory cytokines, free radicals, and fatty acid metabolites. Cytokines and chemokines released from activated microglia induce activation of astrocytes with additional release of proinflammatory mediators that further exacerbates neuroinflammatory response. Dysregulated microglia and T-cell interactions and microglial nodules in the perivascular compartment of the brain were associated with systemic inflammatory conditions in COVID-19 [133][14]. Microglial activation is significantly higher in the brain stem than in non-COVID cases. Further, COVID-19 cases without dementia show more microglial activation in the brain stem [134,135][15][16]. The neuroinflammatory response is indicated by the presence of microglial reactivity indicators such as CD68-positive ameboid microglia, ionized calcium binding adaptor molecule 1 (IBA1), and human leukocyte antigen-DR (HLA-DR) in COVID-19 [132,134][13][15]. COVID-19 shows more T lymphocytes and microthromboses in the lung associated with more microglial activation in the brain stem [135][16]. In other words, the long-term consequences of COVID-19 could be due to persistent inflammation rather than persistent viral replication [135][16]. SARS-CoV-2 induces neuropsychiatric and neurological disorders such as cognitive decline, depression, dizziness, delirium, and sleep disorders that lead to neuronal damage, neurodegenerative disorders, and dementia [136][17]. Thus, SARS-CoV-2 can cause BBB disruption and worsen neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease, especially in aged people [136,137,138][17][18][19].
SARS-CoV-2 infection can cause dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis [139][20], which may be the cause of the emotional changes observed during and after viral infection [140][21]. Several reports have shown the impact of the pandemic on acute and chronic mental health. Further, these studies also focused on the psycho-social factors and stress resilience of mental health and disease pathologies [141,142][22][23]. TLR4 contributes to the immune response and pathogenesis of COVID-19, and thus, TLR4 could be a therapeutic target in COVID-19 [113,143,144][24][25][26]. SARS CoV-2 activates TLR4 and 8 and induces cytokine release from microglia and monocytes [145][27]. Microglia express receptors for neurotensin (NT) [146][28] and corticotropin-releasing hormone (CRH), secreted under stress [147][29], which are especially associated with COVID-19 [148][30]. Microglia are typically characterized as resting (M0), pro-inflammatory (M1), and anti-inflammatory and neuroprotective (M2) phenotypes with different cytokine expressions associated with neuroinflammatory response.
Microglia are increasingly involved in the pathogenesis of psychiatric disorders [132,152,153][13][31][32]. In fact, microglia-induced neuroinflammation was considered a risk factor for the pathogenesis of major depressive disorder [154,155][33][34]. Moreover, SARS-CoV-2 neurotropism may increase the severity of neuropsychiatric issues [156][35]. A recent report indicated that the SARS-CoV-2 protein elicited a robust nuclear factor kappa B (NF-κB)/nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome-mediated pro-inflammatory response and increased Iba1 expression in a BV-2 mouse microglial cell line [84][36]. In addition, post-mortem reports of COVID-19 patients showed significant microglial activation and neuroinflammation associated with brain pathology [157,158,159,160][37][38][39][40]. Increasing reports indicate that elevated inflammatory cytokines and neuroinflammatory responses [72,128,161][8][41][42] can damage brain blood vessels [75,162][43][44] and other brain cells [72[41][45][46],77,78], possibly through abnormally excessive activation of microglia [60,61][47][48]. As such, long COVID could be referred to as “brain autoimmunity” [163][49].

2. Microglia Communicate with Mast Cells

Mast cells communicate with microglia [32[50][51],164], leading to their activation [33,164,165,166][51][52][53][54] and contributing to neuroinflammation [32,33][50][52] and neurodegenerative diseases [32,167][50][55]. This effect is not seen in mast-cell-deficient mice [168,169][56][57]. In fact, mast cell proteases can trigger astrocytes and glia/neurons and release IL-33 [170][58]. Stabilization of mast cells was shown to inhibit lipopolysaccharide (LPS)-induced neuroinflammation by suppressing the activation of microglia [171][59]. Activation of mast cells and microglia in the hypothalamus and brain [172][60] could lead to cognitive dysfunction [173][61] and neuronal apoptosis [173][61]. In addition, mast cells can activate the hypothalamic–pituitary–adrenal (HPA) axis [174,175,176,177][62][63][64][65] through the release of histamine [178][66], IL-6 [179][67], and CRH [180][68]. It is interesting that stress has been linked to the possible priming of immune cells thus contributing to neuroinflammation in AD [181,181][69][69]. Furthermore, NT [182,183][70][71] and substance P (SP) [2][72] induce CRH receptor-1 (CRHR1) expression in mast cells. Mast-cell-derived histamine [184][73] and tryptase [185][74] can trigger microglia and induce neuroinflammation [33][52]. Mast cells have been shown to be an early activator of LPS-induced neuroinflammation and BBB damage in the hippocampus [172][60]. In addition, food allergy that depends on mast cell activation has been shown to increase activated microglia and TNF in the hippocampus, associated with behavioral and learning impairments [186][75]. Another paper reported that early stress in mice and humans disrupted interactions between mast cells and glia via the involvement of histamine [187][76]. As such, mast cells can participate in neuroinflammation [188,189][77][78] by releasing histamine and several inflammatory cytokines and chemokines [190][79].

3. Mast Cells in the CNS

Mast cells are ubiquitous in the body [191][80]. They are mostly known for mediating allergic and anaphylactic reactions [192][81], and several other diseases such as mastocytosis [193][82]. The functions of mast cells in health and several pathologic conditions were reviewed recently [194,195,196,197][83][84][85][86]. Mast cells respond to allergic but also to various other non-allergic stimuli [193][82]. Activated mast cells can secrete as many as 100 biologically powerful mediators, including pro-inflammatory molecules [190][79] such as bradykinin, chymase, histamine, tryptase, chemokine (C-C motif) ligand 2 (CCL2), CXCL8 [198][87], IL-6 [199][88], IL-1β, and TNF-α [200][89]. A particular potent stimulus of the mast cells is the peptide SP, especially when primed by the “alarmin” cytokine IL-33 [201,202,203,204][90][91][92][93]. Mast cells can also be stimulated to secrete mitochondrial DNA (mtDNA) [205][94], which serves as an additional “alarmin” and can trigger an auto-inflammatory reaction [206,207][95][96]. Mast cells are also found in the CNS perivascularly [29[97][98],208], especially in the meninges [28,209][99][100] and the median eminence of the hypothalamus [122[2][100][101],209,210], where they could have numerous functions. Functional interactions have been reported between mast cells and neurons [209,211][100][102] that are often positive for CRH [183,209][71][100]. Mast cells are the richest source of histamine in the CNS, particularly in the amygdala, hippocampus, hypothalamus, and thalamus [212,213][103][104]. Stimulated brain mast cells contribute to postoperative cognitive dysfunction (POCD) through the release of inflammatory and neurotoxic mediators from activated microglia [86,173][61][105]. Activation of mast cells [183][71] and microglia in the hypothalamus [49][106] could cause cognitive dysfunction [173][61] that is also seen in patients with mastocytosis [47,214,215][107][108][109] and may be related to brain abnormalities [216][110]. Allergic stimulation of nasal mast cells resulted in stimulation of the HPA axis [174[62][63][64][65],175,176,177], possibly via mast cell release of histamine [178][66], IL-6 [178[66][111],217], and CRH [180][68]. The influence of stress on mast cells has also been reviewed [140,218][21][112]. Restraint stress in rodents increased BBB permeability [210,219,220][101][113][114] via CRH [219,221,222][113][115][116]. Mast-cell-released cytokines [223,224][117][118] increased BBB permeability [210,219][101][113] and permitted mammary adenocarcinoma brain metastases in mice [221][115]. This process could worsen with stress, acting via CRH stimulation of mast cells [219,221][113][115] and an increase in dura vascular permeability. Meningeal mast cells affected the integrity of the BBB and promoted T-cell brain infiltration [225][119]. Inflammation mediated by mast cells and microglia disrupted the BBB [226][120]. Mast cell responsiveness may be regulated not only by the neuroimmune stimuli but also by the effects of the different receptors involved. For instance, mast cells express high-affinity neurokinin-1 (NK-1) receptors for SP [2][72]. Moreover, SP and NT [182][70] induced the expression of CRHR-1 in human mast cells. Secretion of mediators can occur by utilizing different signaling [227,228,229,230][121][122][123][124] and secretory [228,230][122][124] pathways. The regulation of mast cells by neurotransmitters and neuropeptides has been reviewed [231[125][126][127],232,233], with emphasis on CRH [177][65], hemokinin-1 (HK-1) [234][128], nerve growth factor (NGF [235][129], NT [236][130], SP [237][131], and somatostatin [238,239][132][133] acting via activation of high-affinity receptors. Activated mast cells could release a number of pro-inflammatory and vasoactive mediators that could contribute to long COVID syndrome symptoms [177,240][65][134]. Some mediators are pre-stored in secretory granules (e.g., histamine, tryptase, and TNF-α) [241,242][135][136] and are released immediately following stimulation, while others are newly synthesized and then released, such as chemokines (e.g., CCL2, CCXL8) [198][87], and cytokines (IL-6 [199][88], IL-1β [243][137], TNF-α [200][89]). Apart from allergic triggers acting via IgE, mast cells are stimulated by non-allergic agents [192[81][92][138],203,244], especially neuropeptides [231][125], such as SP [237,243][131][137] and the SP-related HK-1 [234][128], which have pro-inflammatory properties. Under such conditions, especially when primed by IL-33 [203[92][93],204], mast cells can release various inflammatory mediators without the release of histamine or tryptase [245][139], thus contributing to inflammatory disorders [189,192][78][81]. Moreover, mouse mast-cell proteases 6 (MMCP 6) and MMCP 7 stimulated the release of IL-33 from mouse fetal-brain-derived cultured primary astrocytes in vitro [170][58]. A case in point is the selective release of IL-6 [199[88][140],246], which is elevated in systemic mastocytosis and correlated with disease severity [247,248,249][141][142][143] and can increase mast cell numbers [250][144].

4. Mast Cells in Long COVID

Mast cells are activated by viruses [251,252][145][146] such as SARS-CoV-2 [17,18,20,53,55,57,253,254,255,256,257,258,259,260,261][147][148][149][150][151][152][153][154][155][156][157][158][159][160][161]. Recent studies have also reported mast cell activation in the lungs [254][154] and perivascular inflammation in the brains [75][43] of COVID-19 patients. Two studies reported elevated serum levels of chymase in patients with COVID-19 [253,260][153][160]. Moreover, a recent study demonstrated that mast cells enhance cellular entry of SARS-CoV-2 through the generation of chymase-spike complexes [52][162]. Chymase converts angiotensin I to angiotensin II and may act in an autocrine fashion to increase the expression of ACE2, which then facilitate viral entry. Another paper reported that mast-cell-derived histamine can increase SARS-CoV-2 entry into endothelial cells [90][163]. Mast cells also release extracellular mtDNA [205][94], which was shown to be significantly elevated in COVID-19 patients [262][164]. Extracellular mtDNA can then stimulate the secretion of pro-inflammatory mediators from other immunocytes [206,207][95][96].

5. Neuroimmune Biomarkers

While a number of molecules are elevated in the blood of patients with COVID-19 [34[165][166][167][168],35,36,263], the results have been inconsistent and have focused primarily on pro-inflammatory mediators. A few studies have investigated blood biomarkers that may reflect brain injury in COVID-19 patients [264,265][169][170]. Anti-receptor antibodies and autoimmune gene expression [266][171] have also been reported. IL-15 is implicated in viral clearance with anti-viral properties, including in COVID-19 [267,268][172][173]. IL-18 remains elevated longer than other cytokines in inflammatory and autoimmune disorders [270[174][175],271], including COVID-19 [269][176]. Calprotectin (S100A8/A9) was associated with microglia activation [272][177] and was elevated in the serum of patients with COVID-19 [269][176]. Calprotectin was also in the CSF of patients with Multiple Sclerosis (MS) [273][178] and demyelinating polyneuropathy [274][179]. Neuroligins (NLGs) and neurexins are implicated in synaptic function and cognitive disease [275][180]. NLG1 levels were reduced in the cortex and the CSF of AD patients [276][181] or those with mild cognitive impairment (MCI) [277][182]. NLG4 was associated with cognitive decline [278][183], while neuropilin-1 (NRP-1) was shown to facilitate SARS-CoV-2 entry by binding to the spike protein [279][184]. Moreover, S100β was shown to be associated with COVID-19 severity [280][185] and promote microglia activation [281,282,283][186][187][188] and has been linked to neuroinflammation and cognitive decline [284][189]. Neurofilament light chain (NfL), microtubule-associated protein-2 (MAP-2), and glial fibrillary acidic protein (GFAP) indicate axonal/neuronal damage and brain injury [264,285,286,287,288][169][190][191][192][193]. Elevated levels of osteopontin have been associated with reduced cognition [289,290][194][195]. A recent study indicated that COVID-19 was associated with brain pathology in the UK Biobank [291][196] and was associated with neuroinflammation involving primarily the chemokine CCL11 in a mouse model [292][197]. CCL11 has been implicated in neuroinflammatory disorders [293][198], while osteopontin was reported to disrupt the BBB [294][199]. Chemokine CCL19 and its receptor C-C chemokine receptor type 7 (CCR7) axis are involved in the immune response to viral infections [268,295][173][200]. Increased levels of CCL19 were associated with disease severity in COVID-19 patients [296][201].

References

  1. Dos Santos, S.E.; Medeiros, M.; Porfirio, J.; Tavares, W.; Pessoa, L.; Grinberg, L.; Leite, R.E.P.; Ferretti-Rebustini, R.E.L.; Suemoto, C.K.; Filho, W.J.; et al. Similar Microglial Cell Densities across Brain Structures and Mammalian Species: Implications for Brain Tissue Function. J. Neurosci. 2020, 40, 4622–4643.
  2. Colonna, M.; Butovsky, O. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu. Rev. Immunol. 2017, 35, 441–468.
  3. Perry, V.H.; Nicoll, J.A.; Holmes, C. Microglia in neurodegenerative disease. Nat. Rev. Neurol. 2010, 6, 193–201.
  4. Ransohoff, R.M. How neuroinflammation contributes to neurodegeneration. Science 2016, 353, 777–783.
  5. Angelova, D.M.; Brown, D.R. Microglia and the aging brain: Are senescent microglia the key to neurodegeneration? J. Neurochem. 2019, 151, 676–688.
  6. Bachiller, S.; Jimenez-Ferrer, I.; Paulus, A.; Yang, Y.; Swanberg, M.; Deierborg, T.; Boza-Serrano, A. Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response. Front. Cell. Neurosci. 2018, 12, 488.
  7. Hickman, S.; Izzy, S.; Sen, P.; Morsett, L.; El, K.J. Microglia in neurodegeneration. Nat. Neurosci. 2018, 21, 1359–1369.
  8. Liberman, A.C.; Trias, E.; da Silva, C.L.; Trindade, P.; Dos Santos, P.M.; Refojo, D.; Hedin-Pereira, C.; Serfaty, C.A. Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System. Neuroimmunomodulation 2018, 25, 246–270.
  9. Xu, L.; He, D.; Bai, Y. Microglia-Mediated Inflammation and Neurodegenerative Disease. Mol. Neurobiol. 2016, 53, 6709–6715.
  10. Subhramanyam, C.S.; Wang, C.; Hu, Q.; Dheen, S.T. Microglia-mediated neuroinflammation in neurodegenerative diseases. Semin. Cell Dev. Biol. 2019, 94, 112–120.
  11. Voet, S.; Prinz, M.; van Loo, G. Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology. Trends Mol. Med. 2019, 25, 112–123.
  12. Jeong, G.U.; Lyu, J.; Kim, K.D.; Chung, Y.C.; Yoon, G.Y.; Lee, S.; Hwang, I.; Shin, W.H.; Ko, J.; Lee, J.Y.; et al. SARS-CoV-2 Infection of Microglia Elicits Proinflammatory Activation and Apoptotic Cell Death. Microbiol. Spectr. 2022, 10, e0109122.
  13. Goncalves de Andrade, E.; Simoncicova, E.; Carrier, M.; Vecchiarelli, H.A.; Robert, M.E.; Tremblay, M.E. Microglia Fighting for Neurological and Mental Health: On the Central Nervous System Frontline of COVID-19 Pandemic. Front. Cell. Neurosci. 2021, 15, 647378.
  14. Schwabenland, M.; Salie, H.; Tanevski, J.; Killmer, S.; Lago, M.S.; Schlaak, A.E.; Mayer, L.; Matschke, J.; Puschel, K.; Fitzek, A.; et al. Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions. Immunity 2021, 54, 1594–1610.e1511.
  15. Poloni, T.E.; Medici, V.; Moretti, M.; Visona, S.D.; Cirrincione, A.; Carlos, A.F.; Davin, A.; Gagliardi, S.; Pansarasa, O.; Cereda, C.; et al. COVID-19-related neuropathology and microglial activation in elderly with and without dementia. Brain Pathol. 2021, 31, e12997.
  16. Poloni, T.E.; Moretti, M.; Medici, V.; Turturici, E.; Belli, G.; Cavriani, E.; Visona, S.D.; Rossi, M.; Fantini, V.; Ferrari, R.R.; et al. COVID-19 Pathology in the Lung, Kidney, Heart and Brain: The Different Roles of T-Cells, Macrophages, and Microthrombosis. Cells 2022, 11, 3124.
  17. Rai, S.N.; Tiwari, N.; Singh, P.; Singh, A.K.; Mishra, D.; Imran, M.; Singh, S.; Hooshmandi, E.; Vamanu, E.; Singh, S.K.; et al. Exploring the Paradox of COVID-19 in Neurological Complications with Emphasis on Parkinson’s and Alzheimer’s Disease. Oxid. Med. Cell. Longev. 2022, 2022, 3012778.
  18. Baazaoui, N.; Iqbal, K. COVID-19 and Neurodegenerative Diseases: Prion-Like Spread and Long-Term Consequences. J. Alzheimers Dis. 2022, 88, 399–416.
  19. Fu, Y.W.; Xu, H.S.; Liu, S.J. COVID-19 and neurodegenerative diseases. Eur. Rev. Med. Pharmacol. Sci. 2022, 26, 4535–4544.
  20. Steenblock, C.; Todorov, V.; Kanczkowski, W.; Eisenhofer, G.; Schedl, A.; Wong, M.L.; Licinio, J.; Bauer, M.; Young, A.H.; Gainetdinov, R.R.; et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the neuroendocrine stress axis. Mol. Psychiatry 2020, 25, 1611–1617.
  21. Theoharides, T.C. The impact of psychological stress on mast cells. Ann. Allergy Asthma Immunol. 2020, 125, 388–392.
  22. Manchia, M.; Gathier, A.W.; Yapici-Eser, H.; Schmidt, M.V.; de Quervain, D.; van Amelsvoort, T.; Bisson, J.I.; Cryan, J.F.; Howes, O.D.; Pinto, L.; et al. The impact of the prolonged COVID-19 pandemic on stress resilience and mental health: A critical review across waves. Eur. Neuropsychopharmacol. 2022, 55, 22–83.
  23. Lindert, J.; Jakubauskiene, M.; Bilsen, J. The COVID-19 disaster and mental health-assessing, responding and recovering. Eur. J. Public Health 2021, 31 (Suppl. 4), iv31–iv35.
  24. Khanmohammadi, S.; Rezaei, N. Role of Toll-like receptors in the pathogenesis of COVID-19. J. Med. Virol. 2021, 93, 2735–2739.
  25. Dijkstra, A.; Elbert, S.P. Detecting and Preventing Defensive Reactions Toward Persuasive Information on Fruit and Vegetable Consumption Using Induced Eye Movements. Front. Psychol. 2020, 11, 578287.
  26. Patra, R.; Das, N.C.; Mukherjee, S. Toll-Like Receptors (TLRs) as Therapeutic Targets for Treating SARS-CoV-2: An Immunobiological Perspective. Adv. Exp. Med. Biol. 2021, 1352, 87–109.
  27. Wallach, T.; Raden, M.; Hinkelmann, L.; Brehm, M.; Rabsch, D.; Weidling, H.; Kruger, C.; Kettenmann, H.; Backofen, R.; Lehnardt, S. Distinct SARS-CoV-2 RNA fragments activate Toll-like receptors 7 and 8 and induce cytokine release from human macrophages and microglia. Front. Immunol. 2022, 13, 1066456.
  28. Martin, S.; Dicou, E.; Vincent, J.P.; Mazella, J. Neurotensin and the neurotensin receptor-3 in microglial cells. J. Neurosci. Res. 2005, 81, 322–326.
  29. Wang, W.; Ji, P.; Riopelle, R.J.; Dow, K.E. Functional expression of corticotropin-releasing hormone (CRH) receptor 1 in cultured rat microglia. J. Neurochem. 2002, 80, 287–294.
  30. Kempuraj, D.; Selvakumar, G.P.; Ahmed, M.E.; Raikwar, S.P.; Thangavel, R.; Khan, A.; Zaheer, S.A.; Iyer, S.S.; Burton, C.; James, D.; et al. COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation. Neuroscientist 2020, 26, 402–414.
  31. Rahimian, R.; Wakid, M.; O’Leary, L.A.; Mechawar, N. The emerging tale of microglia in psychiatric disorders. Neurosci. Biobehav. Rev. 2021, 131, 1–29.
  32. Wohleb, E.S. Neuron-Microglia Interactions in Mental Health Disorders: “For Better, and For Worse”. Front. Immunol. 2016, 7, 544.
  33. Troubat, R.; Barone, P.; Leman, S.; Desmidt, T.; Cressant, A.; Atanasova, B.; Brizard, B.; El Hage, W.; Surget, A.; Belzung, C.; et al. Neuroinflammation and depression: A review. Eur. J. Neurosci. 2021, 53, 151–171.
  34. Brites, D.; Fernandes, A. Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation. Front. Cell. Neurosci. 2015, 9, 476.
  35. Steardo, L., Jr.; Steardo, L.; Verkhratsky, A. Psychiatric face of COVID-19. Transl. Psychiatry 2020, 10, 261.
  36. Olajide, O.A.; Iwuanyanwu, V.U.; Adegbola, O.D.; Al-Hindawi, A.A. SARS-CoV-2 Spike Glycoprotein S1 Induces Neuroinflammation in BV-2 Microglia. Mol. Neurobiol. 2022, 59, 445–458.
  37. Dixon, L.; Varley, J.; Gontsarova, A.; Mallon, D.; Tona, F.; Muir, D.; Luqmani, A.; Jenkins, I.H.; Nicholas, R.; Jones, B.; et al. COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia. Neurol. Neuroimmunol. Neuroinflamm. 2020, 7, e789.
  38. Boroujeni, M.E.; Simani, L.; Bluyssen, H.A.R.; Samadikhah, H.R.; Zamanlui Benisi, S.; Hassani, S.; Akbari Dilmaghani, N.; Fathi, M.; Vakili, K.; Mahmoudiasl, G.R.; et al. Inflammatory Response Leads to Neuronal Death in Human Post-Mortem Cerebral Cortex in Patients with COVID-19. ACS Chem. Neurosci. 2021, 12, 2143–2150.
  39. Shen, W.B.; Logue, J.; Yang, P.; Baracco, L.; Elahi, M.; Reece, E.A.; Wang, B.; Li, L.; Blanchard, T.G.; Han, Z.; et al. SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology. bioRxiv 2022.
  40. Radhakrishnan, R.K.; Kandasamy, M. SARS-CoV-2-Mediated Neuropathogenesis, Deterioration of Hippocampal Neurogenesis and Dementia. Am. J. Alzheimers Dis. Other Demen. 2022, 37, 15333175221078418.
  41. Karnik, M.; Beeraka, N.M.; Uthaiah, C.A.; Nataraj, S.M.; Bettadapura, A.D.S.; Aliev, G.; Madhunapantula, S.V. A Review on SARS-CoV-2-Induced Neuroinflammation, Neurodevelopmental Complications, and Recent Updates on the Vaccine Development. Mol. Neurobiol. 2021, 58, 4535–4563.
  42. Welcome, M.O.; Mastorakis, N.E. Neuropathophysiology of coronavirus disease 2019: Neuroinflammation and blood brain barrier disruption are critical pathophysiological processes that contribute to the clinical symptoms of SARS-CoV-2 infection. Inflammopharmacology 2021, 29, 939–963.
  43. Lee, M.H.; Perl, D.P.; Nair, G.; Li, W.; Maric, D.; Murray, H.; Dodd, S.J.; Koretsky, A.P.; Watts, J.A.; Cheung, V.; et al. Microvascular Injury in the Brains of Patients with COVID-19. N. Engl. J. Med. 2021, 384, 481–483.
  44. Magro, C.M.; Mulvey, J.; Kubiak, J.; Mikhail, S.; Suster, D.; Crowson, A.N.; Laurence, J.; Nuovo, G. Severe COVID-19: A multifaceted viral vasculopathy syndrome. Ann. Diagn. Pathol. 2021, 50, 151645.
  45. Bodnar, B.; Patel, K.; Ho, W.; Luo, J.J.; Hu, W. Cellular mechanisms underlying neurological/neuropsychiatric manifestations of COVID-19. J. Med. Virol. 2021, 93, 1983–1998.
  46. Ng, J.H.; Sun, A.; Je, H.S.; Tan, E.K. Unravelling Pathophysiology of Neurological and Psychiatric Complications of COVID-19 Using Brain Organoids. Neuroscientist 2021, 29, 30–40.
  47. Tremblay, M.E.; Madore, C.; Bordeleau, M.; Tian, L.; Verkhratsky, A. Neuropathobiology of COVID-19: The Role for Glia. Front. Cell. Neurosci. 2020, 14, 592214.
  48. McMahon, C.L.; Staples, H.; Gazi, M.; Carrion, R.; Hsieh, J. SARS-CoV-2 targets glial cells in human cortical organoids. Stem Cell Rep. 2021, 16, 1156–1164.
  49. Harvey, W.T.; Carabelli, A.M.; Jackson, B.; Gupta, R.K.; Thomson, E.C.; Harrison, E.M.; Ludden, C.; Reeve, R.; Rambaut, A.; Consortium, C.-G.U.; et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat. Rev. Microbiol. 2021, 19, 409–424.
  50. Sandhu, J.K.; Kulka, M. Decoding Mast Cell-Microglia Communication in Neurodegenerative Diseases. Int. J. Mol. Sci. 2021, 22, 1093.
  51. Hendriksen, E.; van Bergeijk, D.; Oosting, R.S.; Redegeld, F.A. Mast cells in neuroinflammation and brain disorders. Neurosci. Biobehav. Rev. 2017, 79, 119–133.
  52. Skaper, S.D.; Facci, L.; Giusti, P. Neuroinflammation, microglia and mast cells in the pathophysiology of neurocognitive disorders: A review. CNS Neurol. Disord. Drug Targets 2014, 13, 1654–1666.
  53. Skaper, S.D.; Facci, L.; Zusso, M.; Giusti, P. Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons. Neuroscientist 2017, 23, 478–498.
  54. Zhang, X.; Wang, Y.; Dong, H.; Xu, Y.; Zhang, S. Induction of Microglial Activation by Mediators Released from Mast Cells. Cell. Physiol. Biochem. 2016, 38, 1520–1531.
  55. Kempuraj, D.; Selvakumar, G.P.; Zaheer, S.; Thangavel, R.; Ahmed, M.E.; Raikwar, S.; Govindarajan, R.; Iyer, S.; Zaheer, A. Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease. J. Neuroimmune Pharmacol. 2018, 13, 100–112.
  56. Dong, H.; Zhang, X.; Wang, Y.; Zhou, X.; Qian, Y.; Zhang, S. Suppression of Brain Mast Cells Degranulation Inhibits Microglial Activation and Central Nervous System Inflammation. Mol. Neurobiol. 2017, 54, 997–1007.
  57. Selvakumar, G.P.; Ahmed, M.E.; Thangavel, R.; Kempuraj, D.; Dubova, I.; Raikwar, S.P.; Zaheer, S.; Iyer, S.S.; Zaheer, A. A role for glia maturation factor dependent activation of mast cells and microglia in MPTP induced dopamine loss and behavioural deficits in mice. Brain Behav. Immun. 2020, 87, 429–443.
  58. Kempuraj, D.; Thangavel, R.; Selvakumar, G.P.; Ahmed, M.E.; Zaheer, S.; Raikwar, S.P.; Zahoor, H.; Saeed, D.; Dubova, I.; Giler, G.; et al. Mast Cell Proteases Activate Astrocytes and Glia-Neurons and Release Interleukin-33 by Activating p38 and ERK1/2 MAPKs and NF-kappaB. Mol. Neurobiol. 2019, 56, 1681–1693.
  59. Dong, H.; Wang, Y.; Zhang, X.; Zhang, X.; Qian, Y.; Ding, H.; Zhang, S. Stabilization of Brain Mast Cells Alleviates LPS-Induced Neuroinflammation by Inhibiting Microglia Activation. Front. Cell. Neurosci. 2019, 13, 191.
  60. Wang, Y.; Sha, H.; Zhou, L.; Chen, Y.; Zhou, Q.; Dong, H.; Qian, Y. The Mast Cell Is an Early Activator of Lipopolysaccharide-Induced Neuroinflammation and Blood-Brain Barrier Dysfunction in the Hippocampus. Mediat. Inflamm. 2020, 2020, 8098439.
  61. Zhang, X.; Dong, H.; Li, N.; Zhang, S.; Sun, J.; Zhang, S.; Qian, Y. Activated brain mast cells contribute to postoperative cognitive dysfunction by evoking microglia activation and neuronal apoptosis 1. J. Neuroinflamm. 2016, 13, 127.
  62. Bugajski, A.J.; Chlap, Z.; Gadek-Michalska, A.; Borycz, J.; Bugajski, J. Degranulation and decrease in histamine levels of thalamic mast cells coincides with corticosterone secretion induced by compound 48/80. Inflamm. Res. 1995, 44 (Suppl. 1), S50–S51.
  63. Kalogeromitros, D.; Syrigou, E.I.; Makris, M.; Kempuraj, D.; Stavrianeas, N.G.; Vasiadi, M.; Theoharides, T.C. Nasal provocation of patients with allergic rhinitis and the hypothalamic-pituitary-adrenal axis. Ann. Allergy Asthma Immunol. 2007, 98, 269–273.
  64. Matsumoto, I.; Inoue, Y.; Shimada, T.; Aikawa, T. Brain mast cells act as an immune gate to the hypothalamic-pituitary-adrenal axis in dogs. J. Exp. Med. 2001, 194, 71–78.
  65. Theoharides, T.C.; Donelan, J.M.; Papadopoulou, N.; Cao, J.; Kempuraj, D.; Conti, P. Mast cells as targets of corticotropin-releasing factor and related peptides. Trends Pharmacol. Sci. 2004, 25, 563–568.
  66. Scaccianoce, S.; Lombardo, K.; Nicolai, R.; Affricano, D.; Angelucci, L. Studies on the involvement of histamine in the hypothalamic-pituitary-adrenal axis activation induced by nerve growth factor. Life Sci. 2000, 67, 3143–3152.
  67. Mastorakos, G.; Chrousos, G.P.; Weber, J.S. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J. Clin. Endocrinol. Metab. 1993, 77, 1690–1694.
  68. Kempuraj, D.; Papadopoulou, N.G.; Lytinas, M.; Huang, M.; Kandere-Grzybowska, K.; Madhappan, B.; Boucher, W.; Christodoulou, S.; Athanassiou, A.; Theoharides, T.C. Corticotropin-releasing hormone and its structurally related urocortin are synthesized and secreted by human mast cells. Endocrinology 2004, 145, 43–48.
  69. Milligan, A.A.; Porter, T.; Quek, H.; White, A.; Haynes, J.; Jackaman, C.; Villemagne, V.; Munyard, K.; Laws, S.M.; Verdile, G.; et al. Chronic stress and Alzheimer’s disease: The interplay between the hypothalamic-pituitary-adrenal axis, genetics and microglia. Biol. Rev. Camb. Philos. Soc. 2021, 96, 2209–2228.
  70. Alysandratos, K.D.; Asadi, S.; Angelidou, A.; Zhang, B.; Sismanopoulos, N.; Yang, H.; Critchfield, A.; Theoharides, T.C. Neurotensin and CRH interactions augment human mast cell activation. PLoS ONE 2012, 7, e48934.
  71. Kempuraj, D.; Mentor, S.; Thangavel, R.; Ahmed, M.E.; Selvakumar, G.P.; Raikwar, S.P.; Dubova, I.; Zaheer, S.; Iyer, S.S.; Zaheer, A. Mast Cells in Stress, Pain, Blood-Brain Barrier, Neuroinflammation and Alzheimer’s Disease. Front. Cell. Neurosci. 2019, 13, 54.
  72. Asadi, S.; Alysandratos, K.D.; Angelidou, A.; Miniati, A.; Sismanopoulos, N.; Vasiadi, M.; Zhang, B.; Kalogeromitros, D.; Theoharides, T.C. Substance P (SP) induces expression of functional corticotropin-releasing hormone receptor-1 (CRHR-1) in human mast cells. J. Investig. Dermatol. 2012, 132, 324–329.
  73. Zhang, W.; Zhang, X.; Zhang, Y.; Qu, C.; Zhou, X.; Zhang, S. Histamine Induces Microglia Activation and the Release of Proinflammatory Mediators in Rat Brain Via H1R or H4R. J. Neuroimmune Pharmacol. 2020, 15, 280–291.
  74. Zhang, S.; Zeng, X.; Yang, H.; Hu, G.; He, S. Mast cell tryptase induces microglia activation via protease-activated receptor 2 signaling. Cell. Physiol. Biochem. 2012, 29, 931–940.
  75. Zhou, L.; Chen, L.; Li, X.; Li, T.; Dong, Z.; Wang, Y.T. Food allergy induces alteration in brain inflammatory status and cognitive impairments. Behav. Brain Res. 2019, 364, 374–382.
  76. McClain, J.L.; Mazzotta, E.A.; Maradiaga, N.; Duque-Wilckens, N.; Grants, I.; Robison, A.J.; Christofi, F.L.; Moeser, A.J.; Gulbransen, B.D. Histamine-dependent interactions between mast cells, glia, and neurons are altered following early-life adversity in mice and humans. Am. J. Physiol. Gastrointest. Liver Physiol. 2020, 319, G655–G668.
  77. Galli, S.J.; Tsai, M.; Piliponsky, A.M. The development of allergic inflammation. Nature 2008, 454, 445–454.
  78. Theoharides, T.C.; Alysandratos, K.D.; Angelidou, A.; Delivanis, D.A.; Sismanopoulos, N.; Zhang, B.; Asadi, S.; Vasiadi, M.; Weng, Z.; Miniati, A.; et al. Mast cells and inflammation. Biochim. Biophys. Acta 2012, 1822, 21–33.
  79. Mukai, K.; Tsai, M.; Saito, H.; Galli, S.J. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol. Rev. 2018, 282, 121–150.
  80. Gurish, M.F.; Austen, K.F. Developmental origin and functional specialization of mast cell subsets 1. Immunity 2012, 37, 25–33.
  81. Olivera, A.; Beaven, M.A.; Metcalfe, D.D. Mast cells signal their importance in health and disease. J. Allergy Clin. Immunol. 2018, 142, 381–393.
  82. Theoharides, T.C.; Valent, P.; Akin, C. Mast Cells, Mastocytosis, and Related Disorders. N. Engl. J. Med. 2015, 373, 163–172.
  83. Falduto, G.H.; Pfeiffer, A.; Luker, A.; Metcalfe, D.D.; Olivera, A. Emerging mechanisms contributing to mast cell-mediated pathophysiology with therapeutic implications. Pharmacol. Ther. 2021, 220, 107718.
  84. Levi-Schaffer, F.; Gibbs, B.F.; Hallgren, J.; Pucillo, C.; Redegeld, F.; Siebenhaar, F.; Vitte, J.; Mezouar, S.; Michel, M.; Puzzovio, P.G.; et al. Selected recent advances in understanding the role of human mast cells in health and disease. J. Allergy Clin. Immunol. 2022, 149, 1833–1844.
  85. Kolkhir, P.; Elieh-Ali-Komi, D.; Metz, M.; Siebenhaar, F.; Maurer, M. Understanding human mast cells: Lesson from therapies for allergic and non-allergic diseases. Nat. Rev. Immunol. 2022, 22, 294–308.
  86. Dahlin, J.S.; Maurer, M.; Metcalfe, D.D.; Pejler, G.; Sagi-Eisenberg, R.; Nilsson, G. The ingenious mast cell: Contemporary insights into mast cell behavior and function. Allergy 2022, 77, 83–99.
  87. Bawazeer, M.A.; Theoharides, T.C. IL-33 stimulates human mast cell release of CCL5 and CCL2 via MAPK and NF-kappaB, inhibited by methoxyluteolin. Eur. J. Pharmacol. 2019, 865, 172760.
  88. Kandere-Grzybowska, K.; Letourneau, R.; Kempuraj, D.; Donelan, J.; Poplawski, S.; Boucher, W.; Athanassiou, A.; Theoharides, T.C. IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells. J. Immunol. 2003, 171, 4830–4836.
  89. Taracanova, A.; Alevizos, M.; Karagkouni, A.; Weng, Z.; Norwitz, E.; Conti, P.; Leeman, S.E.; Theoharides, T.C. SP and IL-33 together markedly enhance TNF synthesis and secretion from human mast cells mediated by the interaction of their receptors. Proc. Natl. Acad. Sci. USA 2017, 114, E4002–E4009.
  90. Theoharides, T.C.; Petra, A.I.; Taracanova, A.; Panagiotidou, S.; Conti, P. Targeting IL-33 in autoimmunity and inflammation. J. Pharmacol. Exp. Ther. 2015, 354, 24–31.
  91. Liew, F.Y.; Pitman, N.I.; McInnes, I.B. Disease-associated functions of IL-33: The new kid in the IL-1 family. Nat. Rev. Immunol. 2010, 10, 103–110.
  92. Theoharides, T.C.; Leeman, S.E. Effect of IL-33 on de novo synthesized mediators from human mast cells. J. Allergy Clin. Immunol. 2019, 143, 451.
  93. Saluja, R.; Khan, M.; Church, M.K.; Maurer, M. The role of IL-33 and mast cells in allergy and inflammation. Clin. Transl. Allergy 2015, 5, 33.
  94. Zhang, B.; Asadi, S.; Weng, Z.; Sismanopoulos, N.; Theoharides, T.C. Stimulated human mast cells secrete mitochondrial components that have autocrine and paracrine inflammatory actions. PLoS ONE 2012, 7, e49767.
  95. Collins, L.V.; Hajizadeh, S.; Holme, E.; Jonsson, I.M.; Tarkowski, A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J. Leukoc. Biol. 2004, 75, 995–1000.
  96. Sun, S.; Sursal, T.; Adibnia, Y.; Zhao, C.; Zheng, Y.; Li, H.; Otterbein, L.E.; Hauser, C.J.; Itagaki, K. Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways. PLoS ONE 2013, 8, e59989.
  97. Theoharides, T.C. Mast cells: The immune gate to the brain. Life Sci. 1990, 46, 607–617.
  98. Traina, G. Mast cells in the brain—Old cells, new target. J. Integr. Neurosci. 2017, 16, S69–S83.
  99. Polyzoidis, S.; Koletsa, T.; Panagiotidou, S.; Ashkan, K.; Theoharides, T.C. Mast cells in meningiomas and brain inflammation. J. Neuroinflamm. 2015, 12, 170.
  100. Rozniecki, J.J.; Dimitriadou, V.; Lambracht-Hall, M.; Pang, X.; Theoharides, T.C. Morphological and functional demonstration of rat dura mater mast cell-neuron interactions in vitro and in vivo. Brain Res. 1999, 849, 1–15.
  101. Theoharides, T.C.; Konstantinidou, A.D. Corticotropin-releasing hormone and the blood-brain-barrier. Front. Biosci. 2007, 12, 1615–1628.
  102. Dimitriadou, V.; Rouleau, A.; Trung Tuong, M.D.; Newlands, G.J.; Miller, H.R.; Luffau, G.; Schwartz, J.C.; Garbarg, M. Functional relationships between sensory nerve fibers and mast cells of dura mater in normal and inflammatory conditions. Neuroscience 1997, 77, 829–839.
  103. Torrealba, F.; Riveros, M.E.; Contreras, M.; Valdes, J.L. Histamine and motivation. Front. Syst. Neurosci. 2012, 6, 51.
  104. Nomura, H.; Shimizume, R.; Ikegaya, Y. Histamine: A Key Neuromodulator of Memory Consolidation and Retrieval. Curr. Top. Behav. Neurosci. 2021, 59, 329–353.
  105. Frank, M.G.; Nguyen, K.H.; Ball, J.B.; Hopkins, S.; Kelley, T.; Baratta, M.V.; Fleshner, M.; Maier, S.F. SARS-CoV-2 spike S1 subunit induces neuroinflammatory, microglial and behavioral sickness responses: Evidence of PAMP-like properties. Brain Behav. Immun. 2022, 100, 267–277.
  106. Hatziagelaki, E.; Adamaki, M.; Tsilioni, I.; Dimitriadis, G.; Theoharides, T.C. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus? J. Pharmacol. Exp. Ther. 2018, 367, 155–167.
  107. Afrin, L.B.; Pohlau, D.; Raithel, M.; Haenisch, B.; Dumoulin, F.L.; Homann, J.; Mauer, U.M.; Harzer, S.; Molderings, G.J. Mast cell activation disease: An underappreciated cause of neurologic and psychiatric symptoms and diseases. Brain Behav. Immun. 2015, 50, 314–321.
  108. Moura, D.S.; Sultan, S.; Georgin-Lavialle, S.; Barete, S.; Lortholary, O.; Gaillard, R.; Hermine, O. Evidence for cognitive impairment in mastocytosis: Prevalence, features and correlations to depression. PLoS ONE 2012, 7, e39468.
  109. Spolak-Bobryk, N.; Romantowski, J.; Kujawska-Danecka, H.; Niedoszytko, M. Mastocytosis patients’ cognitive dysfunctions correlate with the presence of spindle-shaped mast cells in bone marrow. Clin. Transl. Allergy 2022, 12, e12093.
  110. Boddaert, N.; Salvador, A.; Chandesris, M.O.; Lemaitre, H.; Grevent, D.; Gauthier, C.; Naggara, O.; Georgin-Lavialle, S.; Moura, D.S.; Munsch, F.; et al. Neuroimaging evidence of brain abnormalities in mastocytosis. Transl. Psychiatry 2017, 7, e1197.
  111. Spath-Schwalbe, E.; Born, J.; Schrezenmeier, H.; Bornstein, S.R.; Stromeyer, P.; Drechsler, S.; Fehm, H.L.; Porzsolt, F. Interleukin-6 stimulates the hypothalamus-pituitary-adrenocortical axis in man. J. Clin. Endocrinol. Metab. 1994, 79, 1212–1214.
  112. Theoharides, T.C. Effect of Stress on Neuroimmune Processes. Clin. Ther. 2020, 42, 1007–1014.
  113. Esposito, P.; Chandler, N.; Kandere, K.; Basu, S.; Jacobson, S.; Connolly, R.; Tutor, D.; Theoharides, T.C. Corticotropin-releasing hormone and brain mast cells regulate blood-brain-barrier permeability induced by acute stress. J. Pharmacol. Exp. Ther. 2002, 303, 1061–1066.
  114. Fiorentino, M.; Sapone, A.; Senger, S.; Camhi, S.S.; Kadzielski, S.M.; Buie, T.M.; Kelly, D.L.; Cascella, N.; Fasano, A. Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders. Mol. Autism 2016, 7, 49.
  115. Rozniecki, J.J.; Sahagian, G.G.; Kempuraj, D.; Tao, K.; Jocobson, S.; Zhang, B.; Theoharides, T.C. Brain metastases of mouse mammary adenocarcinoma is increased by acute stress. Brain Res. 2010, 1366, 204–210.
  116. Theoharides, T.C.; Rozniecki, J.J.; Sahagian, G.; Jocobson, S.; Kempuraj, D.; Conti, P.; Kalogeromitros, D. Impact of stress and mast cells on brain metastases. J. Neuroimmunol. 2008, 205, 1–7.
  117. Abbott, N.J. Inflammatory mediators and modulation of blood-brain barrier permeability. Cell Mol. Neurobiol. 2000, 20, 131–147.
  118. Pan, W.; Stone, K.P.; Hsuchou, H.; Manda, V.K.; Zhang, Y.; Kastin, A.J. Cytokine signaling modulates blood-brain barrier function. Curr. Pharm. Des. 2011, 17, 3729–3740.
  119. Sayed, B.A.; Christy, A.L.; Walker, M.E.; Brown, M.A. Meningeal mast cells affect early T cell central nervous system infiltration and blood-brain barrier integrity through TNF: A role for neutrophil recruitment? J. Immunol. 2010, 184, 6891–6900.
  120. Skaper, S.D. Impact of Inflammation on the Blood-Neural Barrier and Blood-Nerve Interface: From Review to Therapeutic Preview. Int. Rev. Neurobiol. 2017, 137, 29–45.
  121. Sibilano, R.; Frossi, B.; Pucillo, C.E. Mast cell activation: A complex interplay of positive and negative signaling pathways. Eur. J. Immunol. 2014, 44, 2558–2566.
  122. Xu, H.; Bin, N.R.; Sugita, S. Diverse exocytic pathways for mast cell mediators. Biochem. Soc. Trans. 2018, 46, 235–247.
  123. Gilfillan, A.M.; Tkaczyk, C. Integrated signalling pathways for mast-cell activation. Nat. Rev. Immunol 2006, 6, 218–230.
  124. Gaudenzio, N.; Sibilano, R.; Marichal, T.; Starkl, P.; Reber, L.L.; Cenac, N.; McNeil, B.D.; Dong, X.; Hernandez, J.D.; Sagi-Eisenberg, R.; et al. Different activation signals induce distinct mast cell degranulation strategies. J. Clin. Investig. 2016, 126, 3981–3998.
  125. Theoharides, T.C. Neuroendocrinology of mast cells: Challenges and controversies. Exp. Dermatol. 2017, 26, 751–759.
  126. Theoharides, T.C.; Tsilioni, I.; Bawazeer, M. Mast Cells, Neuroinflammation and Pain in Fibromyalgia Syndrome. Front. Cell. Neurosci. 2019, 13, 353.
  127. Xu, H.; Shi, X.; Li, X.; Zou, J.; Zhou, C.; Liu, W.; Shao, H.; Chen, H.; Shi, L. Neurotransmitter and neuropeptide regulation of mast cell function: A systematic review. J. Neuroinflamm. 2020, 17, 356.
  128. Sumpter, T.L.; Ho, C.H.; Pleet, A.R.; Tkacheva, O.A.; Shufesky, W.J.; Rojas-Canales, D.M.; Morelli, A.E.; Larregina, A.T. Autocrine hemokinin-1 functions as an endogenous adjuvant for IgE-mediated mast cell inflammatory responses. J. Allergy Clin. Immunol. 2015, 135, 1019–1030.
  129. Levi-Montalcini, R.; Skaper, S.D.; Dal Toso, R.; Petrelli, L.; Leon, A. Nerve growth factor: From neurotrophin to neurokine. Trends Neurosci. 1996, 19, 514–520.
  130. Donelan, J.; Boucher, W.; Papadopoulou, N.; Lytinas, M.; Papaliodis, D.; Dobner, P.; Theoharides, T.C. Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process. Proc. Natl. Acad. Sci. USA 2006, 103, 7759–7764.
  131. Theoharides, T.C.; Zhang, B.; Kempuraj, D.; Tagen, M.; Vasiadi, M.; Angelidou, A.; Alysandratos, K.D.; Kalogeromitros, D.; Asadi, S.; Stavrianeas, N.; et al. IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc. Natl. Acad. Sci. USA 2010, 107, 4448–4453.
  132. Theoharides, T.C.; Betchaku, T.; Douglas, W.W. Somatostatin-induced histamine secretion in mast cells. Characterization of the effect. Eur. J. Pharmacol. 1981, 69, 127–137.
  133. Theoharides, T.C.; Douglas, W.W. Mast cell histamine secretion in response to somatostatin analogues: Structural considerations. Eur. J. Pharmacol. 1981, 73, 131–136.
  134. Theoharides, T.C.; Papaliodis, D.; Tagen, M.; Konstantinidou, A.; Kempuraj, D.; Clemons, A. Chronic fatigue syndrome, mast cells, and tricyclic antidepressants. J. Clin. Psychopharmacol. 2005, 25, 515–520.
  135. Gordon, J.R.; Galli, S.J. Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin. Nature 1990, 346, 274–276.
  136. Zhang, B.; Alysandratos, K.D.; Angelidou, A.; Asadi, S.; Sismanopoulos, N.; Delivanis, D.A.; Weng, Z.; Miniati, A.; Vasiadi, M.; Katsarou-Katsari, A.; et al. Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: Relevance to atopic dermatitis. J. Allergy Clin. Immunol. 2011, 127, 1522–1531.e1528.
  137. Taracanova, A.; Tsilioni, I.; Conti, P.; Norwitz, E.R.; Leeman, S.E.; Theoharides, T.C. Substance P and IL-33 administered together stimulate a marked secretion of IL-1beta from human mast cells, inhibited by methoxyluteolin. Proc. Natl. Acad. Sci. USA 2018, 115, E9381–E9390.
  138. Yu, Y.; Blokhuis, B.R.; Garssen, J.; Redegeld, F.A. Non-IgE mediated mast cell activation. Eur. J. Pharmacol. 2016, 778, 33–43.
  139. Theoharides, T.C.; Kempuraj, D.; Tagen, M.; Conti, P.; Kalogeromitros, D. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol. Rev. 2007, 217, 65–78.
  140. Gagari, E.; Tsai, M.; Lantz, C.S.; Fox, L.G.; Galli, S.J. Differential release of mast cell interleukin-6 via c-kit. Blood 1997, 89, 2654–2663.
  141. Theoharides, T.C.; Boucher, W.; Spear, K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int. Arch. Allergy Immunol. 2002, 128, 344–350.
  142. Brockow, K.; Akin, C.; Huber, M.; Metcalfe, D.D. IL-6 levels predict disease variant and extent of organ involvement in patients with mastocytosis. Clin. Immunol. 2005, 115, 216–223.
  143. Mayado, A.; Teodosio, C.; Garcia-Montero, A.C.; Matito, A.; Rodriguez-Caballero, A.; Morgado, J.M.; Muniz, C.; Jara-Acevedo, M.; Alvarez-Twose, I.; Sanchez-Munoz, L.; et al. Increased IL6 plasma levels in indolent systemic mastocytosis patients are associated with high risk of disease progression. Leukemia 2016, 30, 124–130.
  144. Kaur, D.; Gomez, E.; Doe, C.; Berair, R.; Woodman, L.; Saunders, R.; Hollins, F.; Rose, F.R.; Amrani, Y.; May, R.; et al. IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: Airway smooth muscle crosstalk. Allergy 2015, 70, 556–567.
  145. Abraham, S.N.; St John, A.L. Mast cell-orchestrated immunity to pathogens. Nat. Rev. Immunol. 2010, 10, 440–452.
  146. Song, S.T.; Wu, M.L.; Zhang, H.J.; Su, X.; Wang, J.H. Mast Cell Activation Triggered by Retrovirus Promotes Acute Viral Infection. Front. Microbiol. 2022, 13, 798660.
  147. Theoharides, T.C. Potential association of mast cells with coronavirus disease 2019. Ann. Allergy Asthma Immunol. 2021, 126, 217–218.
  148. Theoharides, T.C. COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin. Biofactors 2020, 46, 306–308.
  149. Weinstock, L.B.; Brook, J.B.; Walters, A.S.; Goris, A.; Afrin, L.B.; Molderings, G.J. Mast cell activation symptoms are prevalent in Long-COVID. Int. J. Infect. Dis. 2021, 112, 217–226.
  150. Arun, S.; Storan, A.; Myers, B. Mast cell activation syndrome and the link with long COVID. Br. J. Hosp. Med. 2022, 83, 1–10.
  151. Afrin, L.B.; Weinstock, L.B.; Molderings, G.J. COVID-19 hyperinflammation and post-COVID-19 illness may be rooted in mast cell activation syndrome. Int. J. Infect. Dis. 2020, 100, 327–332.
  152. Hafezi, B.; Chan, L.; Knapp, J.P.; Karimi, N.; Alizadeh, K.; Mehrani, Y.; Bridle, B.W.; Karimi, K. Cytokine Storm Syndrome in SARS-CoV-2 Infections: A Functional Role of Mast Cells. Cells 2021, 10, 1761.
  153. Gebremeskel, S.; Schanin, J.; Coyle, K.M.; Butuci, M.; Luu, T.; Brock, E.C.; Xu, A.; Wong, A.; Leung, J.; Korver, W.; et al. Mast Cell and Eosinophil Activation Are Associated With COVID-19 and TLR-Mediated Viral Inflammation: Implications for an Anti-Siglec-8 Antibody. Front. Immunol. 2021, 12, 650331.
  154. Motta Junior, J.D.S.; Miggiolaro, A.; Nagashima, S.; de Paula, C.B.V.; Baena, C.P.; Scharfstein, J.; de Noronha, L. Mast Cells in Alveolar Septa of COVID-19 Patients: A Pathogenic Pathway That May Link Interstitial Edema to Immunothrombosis. Front. Immunol. 2020, 11, 574862.
  155. Wu, M.L.; Liu, F.L.; Sun, J.; Li, X.; He, X.Y.; Zheng, H.Y.; Zhou, Y.H.; Yan, Q.; Chen, L.; Yu, G.Y.; et al. SARS-CoV-2-triggered mast cell rapid degranulation induces alveolar epithelial inflammation and lung injury. Signal Transduct. Target. Ther. 2021, 6, 428.
  156. Tan, J.; Anderson, D.E.; Rathore, A.P.S.; O’Neill, A.; Mantri, C.K.; Saron, W.A.A.; Lee, C.; Cui, C.W.; Kang, A.E.Z.; Foo, R.; et al. Signatures of mast cell activation are associated with severe COVID-19. medRxiv 2021.
  157. Zelechowska, P.; Brzezinska-Blaszczyk, E.; Agier, J.; Kozlowska, E. Different effectiveness of fungal pathogen-associated molecular patterns (PAMPs) in activating rat peritoneal mast cells. Immunol. Lett. 2022, 248, 7–15.
  158. Krysko, O.; Bourne, J.H.; Kondakova, E.; Galova, E.A.; Whitworth, K.; Newby, M.L.; Bachert, C.; Hill, H.; Crispin, M.; Stamataki, Z.; et al. Severity of SARS-CoV-2 infection is associated with high numbers of alveolar mast cells and their degranulation. Front. Immunol. 2022, 13, 968981.
  159. Takagi, D.; Ishiyama, K.; Suganami, M.; Ushijima, T.; Fujii, T.; Tazoe, Y.; Kawasaki, M.; Noguchi, K.; Makino, A. Manganese toxicity disrupts indole acetic acid homeostasis and suppresses the CO(2) assimilation reaction in rice leaves. Sci. Rep. 2021, 11, 20922.
  160. Wechsler, J.B.; Butuci, M.; Wong, A.; Kamboj, A.P.; Youngblood, B.A. Mast cell activation is associated with post-acute COVID-19 syndrome. Allergy 2022, 77, 1288–1291.
  161. da Silveira Gorman, R.; Syed, I.U. Connecting the Dots in Emerging Mast Cell Research: Do Factors Affecting Mast Cell Activation Provide a Missing Link between Adverse COVID-19 Outcomes and the Social Determinants of Health? Med. Sci. 2022, 10, 29.
  162. Liu, S.; Suzuki, Y.; Takemasa, E.; Watanabe, R.; Mogi, M. Mast cells promote viral entry of SARS-CoV-2 via formation of chymase/spike protein complex. Eur. J. Pharmacol. 2022, 930, 175169.
  163. Raghavan, S.; Leo, M.D. Histamine Potentiates SARS-CoV-2 Spike Protein Entry Into Endothelial Cells. Front. Pharmacol. 2022, 13, 872736.
  164. Scozzi, D.; Cano, M.; Ma, L.; Zhou, D.; Zhu, J.H.; O’Halloran, J.A.; Goss, C.; Rauseo, A.M.; Liu, Z.; Sahu, S.K.; et al. Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19. JCI Insight 2021, 6, e143299.
  165. Cron, R.Q.; Goyal, G.; Chatham, W.W. Cytokine Storm Syndrome. Annu. Rev. Med. 2022, 74, 321–337.
  166. Dutta, D.; Liu, J.; Xiong, H. NLRP3 inflammasome activation and SARS-CoV-2-mediated hyperinflammation, cytokine storm and neurological syndromes. Int. J. Physiol. Pathophysiol. Pharmacol. 2022, 14, 138–160.
  167. Rasool, G.; Riaz, M.; Abbas, M.; Fatima, H.; Qamar, M.M.; Zafar, F.; Mahmood, Z. COVID-19: Clinical laboratory diagnosis and monitoring of novel coronavirus infected patients using molecular, serological and biochemical markers: A review. Int. J. Immunopathol. Pharmacol. 2022, 36, 3946320221115316.
  168. Keykavousi, K.; Nourbakhsh, F.; Abdollahpour, N.; Fazeli, F.; Sedaghat, A.; Soheili, V.; Sahebkar, A. A Review of Routine Laboratory Biomarkers for the Detection of Severe COVID-19 Disease. Int. J. Anal. Chem. 2022, 2022, 9006487.
  169. DeKosky, S.T.; Kochanek, P.M.; Valadka, A.B.; Clark, R.S.B.; Chou, S.H.; Au, A.K.; Horvat, C.; Jha, R.M.; Mannix, R.; Wisniewski, S.R.; et al. Blood Biomarkers for Detection of Brain Injury in COVID-19 Patients. J. Neurotrauma 2021, 38, 1–43.
  170. Frontera, J.A.; Boutajangout, A.; Masurkar, A.V.; Betensky, R.A.; Ge, Y.; Vedvyas, A.; Debure, L.; Moreira, A.; Lewis, A.; Huang, J.; et al. Comparison of serum neurodegenerative biomarkers among hospitalized COVID-19 patients versus non-COVID subjects with normal cognition, mild cognitive impairment, or Alzheimer’s dementia. Alzheimers Dement. 2022, 18, 899–910.
  171. Wang, Z.; Waldman, M.F.; Basavanhally, T.J.; Jacobs, A.R.; Lopez, G.; Perichon, R.Y.; Ma, J.J.; Mackenzie, E.M.; Healy, J.B.; Wang, Y.; et al. Autoimmune gene expression profiling of fingerstick whole blood in Chronic Fatigue Syndrome. J. Transl. Med. 2022, 20, 486.
  172. Kandikattu, H.K.; Venkateshaiah, S.U.; Kumar, S.; Mishra, A. IL-15 immunotherapy is a viable strategy for COVID-19. Cytokine Growth Factor Rev. 2020, 54, 24–31.
  173. Lu, T.; Ma, R.; Dong, W.; Teng, K.Y.; Kollath, D.S.; Li, Z.; Yi, J.; Bustillos, C.; Ma, S.; Tian, L.; et al. Off-the-shelf CAR natural killer cells secreting IL-15 target spike in treating COVID-19. Nat. Commun. 2022, 13, 2576.
  174. Yasuda, K.; Nakanishi, K.; Tsutsui, H. Interleukin-18 in Health and Disease. Int. J. Mol. Sci. 2019, 20, 649.
  175. Ihim, S.A.; Abubakar, S.D.; Zian, Z.; Sasaki, T.; Saffarioun, M.; Maleknia, S.; Azizi, G. Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment. Front. Immunol. 2022, 13, 919973.
  176. Kassianidis, G.; Siampanos, A.; Poulakou, G.; Adamis, G.; Rapti, A.; Milionis, H.; Dalekos, G.N.; Petrakis, V.; Sympardi, S.; Metallidis, S.; et al. Calprotectin and Imbalances between Acute-Phase Mediators Are Associated with Critical Illness in COVID-19. Int. J. Mol. Sci. 2022, 23, 4894.
  177. Wu, M.; Xu, L.; Wang, Y.; Zhou, N.; Zhen, F.; Zhang, Y.; Qu, X.; Fan, H.; Liu, S.; Chen, Y.; et al. S100A8/A9 induces microglia activation and promotes the apoptosis of oligodendrocyte precursor cells by activating the NF-kappaB signaling pathway. Brain Res. Bull. 2018, 143, 234–245.
  178. Berg-Hansen, P.; Vandvik, B.; Fagerhol, M.; Holmoy, T. Calprotectin levels in the cerebrospinal fluid reflect disease activity in multiple sclerosis. J. Neuroimmunol. 2009, 216, 98–102.
  179. Stascheit, F.; Hotter, B.; Klose, S.; Meisel, C.; Meisel, A.; Klehmet, J. Calprotectin in Chronic Inflammatory Demyelinating Polyneuropathy and Variants-A Potential Novel Biomarker of Disease Activity. Front. Neurol. 2021, 12, 723009.
  180. Sudhof, T.C. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 2008, 455, 903–911.
  181. Camporesi, E.; Lashley, T.; Gobom, J.; Lantero-Rodriguez, J.; Hansson, O.; Zetterberg, H.; Blennow, K.; Becker, B. Neuroligin-1 in brain and CSF of neurodegenerative disorders: Investigation for synaptic biomarkers. Acta Neuropathol. Commun. 2021, 9, 19.
  182. Dufort-Gervais, J.; Provost, C.; Charbonneau, L.; Norris, C.M.; Calon, F.; Mongrain, V.; Brouillette, J. Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers. Sci. Rep. 2020, 10, 6956.
  183. Zhang, K.; Gao, X.; Qi, H.; Li, J.; Zheng, Z.; Zhang, F. Gender differences in cognitive ability associated with genetic variants of NLGN4. Neuropsychobiology 2010, 62, 221–228.
  184. Cantuti-Castelvetri, L.; Ojha, R.; Pedro, L.D.; Djannatian, M.; Franz, J.; Kuivanen, S.; van der Meer, F.; Kallio, K.; Kaya, T.; Anastasina, M.; et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 2020, 370, 856–860.
  185. Aceti, A.; Margarucci, L.M.; Scaramucci, E.; Orsini, M.; Salerno, G.; Di Sante, G.; Gianfranceschi, G.; Di Liddo, R.; Valeriani, F.; Ria, F.; et al. Serum S100B protein as a marker of severity in COVID-19 patients. Sci. Rep. 2020, 10, 18665.
  186. Zhou, S.; Zhu, W.; Zhang, Y.; Pan, S.; Bao, J. S100B promotes microglia M1 polarization and migration to aggravate cerebral ischemia. Inflamm. Res. 2018, 67, 937–949.
  187. Xu, J.; Wang, H.; Won, S.J.; Basu, J.; Kapfhamer, D.; Swanson, R.A. Microglial activation induced by the alarmin S100B is regulated by poly(ADP-ribose) polymerase-1. Glia 2016, 64, 1869–1878.
  188. Bianchi, R.; Kastrisianaki, E.; Giambanco, I.; Donato, R. S100B protein stimulates microglia migration via RAGE-dependent up-regulation of chemokine expression and release. J. Biol. Chem. 2011, 286, 7214–7226.
  189. Hopman, J.H.; Santing, J.A.L.; Foks, K.A.; Verheul, R.J.; van der Linden, C.M.; van den Brand, C.L.; Jellema, K. Biomarker S100B in plasma a screening tool for mild traumatic brain injury in an emergency department. Brain Inj 2023, 37, 47–53.
  190. Shahim, P.; Politis, A.; van der Merwe, A.; Moore, B.; Chou, Y.Y.; Pham, D.L.; Butman, J.A.; Diaz-Arrastia, R.; Gill, J.M.; Brody, D.L.; et al. Neurofilament light as a biomarker in traumatic brain injury. Neurology 2020, 95, e610–e622.
  191. Savarraj, J.; Park, E.S.; Colpo, G.D.; Hinds, S.N.; Morales, D.; Ahnstedt, H.; Paz, A.S.; Assing, A.; Liu, F.; Juneja, S.; et al. Brain injury, endothelial injury and inflammatory markers are elevated and express sex-specific alterations after COVID-19. J. Neuroinflamm. 2021, 18, 277.
  192. Park, D.; Joo, S.S.; Lee, H.J.; Choi, K.C.; Kim, S.U.; Kim, Y.B. Microtubule-associated protein 2, an early blood marker of ischemic brain injury. J. Neurosci. Res. 2012, 90, 461–467.
  193. Hicks, C.; Dhiman, A.; Barrymore, C.; Goswami, T. Traumatic Brain Injury Biomarkers, Simulations and Kinetics. Bioengineering 2022, 9, 612.
  194. Iaffaldano, P.; Ruggieri, M.; Viterbo, R.G.; Mastrapasqua, M.; Trojano, M. The improvement of cognitive functions is associated with a decrease of plasma Osteopontin levels in Natalizumab treated relapsing multiple sclerosis. Brain Behav. Immun. 2014, 35, 176–181.
  195. Chai, Y.L.; Chong, J.R.; Raquib, A.R.; Xu, X.; Hilal, S.; Venketasubramanian, N.; Tan, B.Y.; Kumar, A.P.; Sethi, G.; Chen, C.P.; et al. Plasma osteopontin as a biomarker of Alzheimer’s disease and vascular cognitive impairment. Sci. Rep. 2021, 11, 4010.
  196. Khalifa, S.; Holmstead, R.L.; Casida, J.E. Toxaphene degradation by iron(II) protoporphyrin systems. J. Agric. Food Chem. 1976, 24, 277–282.
  197. Fernandez-Castaneda, A.; Lu, P.; Geraghty, A.C.; Song, E.; Lee, M.H.; Wood, J.; O’Dea, M.R.; Dutton, S.; Shamardani, K.; Nwangwu, K.; et al. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell 2022, 185, 2452–2468.e2416.
  198. Nazarinia, D.; Behzadifard, M.; Gholampour, J.; Karimi, R.; Gholampour, M. Eotaxin-1 (CCL11) in neuroinflammatory disorders and possible role in COVID-19 neurologic complications. Acta Neurol. Belg. 2022, 122, 865–869.
  199. Spitzer, D.; Guerit, S.; Puetz, T.; Khel, M.I.; Armbrust, M.; Dunst, M.; Macas, J.; Zinke, J.; Devraj, G.; Jia, X.; et al. Profiling the neurovascular unit unveils detrimental effects of osteopontin on the blood-brain barrier in acute ischemic stroke. Acta Neuropathol. 2022, 144, 305–337.
  200. Yan, Y.; Chen, R.; Wang, X.; Hu, K.; Huang, L.; Lu, M.; Hu, Q. CCL19 and CCR7 Expression, Signaling Pathways, and Adjuvant Functions in Viral Infection and Prevention. Front. Cell. Dev. Biol. 2019, 7, 212.
  201. Tveita, A.; Murphy, S.L.; Holter, J.C.; Kildal, A.B.; Michelsen, A.E.; Lerum, T.V.; Kaarbo, M.; Heggelund, L.; Holten, A.R.; Finbraten, A.K.; et al. High circulating levels of the homeostatic chemokines CCL19 and CCL21 predict mortality and disease severity in COVID-19. J. Infect. Dis. 2022, 226, 2150–2160.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback