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D'avila, J. Microglia in Sepsis-Associated Encephalopathy. Encyclopedia. Available online: https://encyclopedia.pub/entry/9671 (accessed on 23 July 2024).
D'avila J. Microglia in Sepsis-Associated Encephalopathy. Encyclopedia. Available at: https://encyclopedia.pub/entry/9671. Accessed July 23, 2024.
D'avila, Joana. "Microglia in Sepsis-Associated Encephalopathy" Encyclopedia, https://encyclopedia.pub/entry/9671 (accessed July 23, 2024).
D'avila, J. (2021, May 16). Microglia in Sepsis-Associated Encephalopathy. In Encyclopedia. https://encyclopedia.pub/entry/9671
D'avila, Joana. "Microglia in Sepsis-Associated Encephalopathy." Encyclopedia. Web. 16 May, 2021.
Microglia in Sepsis-Associated Encephalopathy
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This entry is adapted from the peer-reviewed paper 10.3390/ph14050416

Multiple organ dysfunction is a hallmark of sepsis pathogenesis, and neurological manifestations are a frequent and underestimated symptom. Sepsis induces an acute brain dysfunction that is not related to direct brain infection and is characterized by clinical and electroencephalographic changes that range from sickness behavior to altered consciousness, varying from confusion to delirium and coma.

Microglia Sepsis-Associated Encephalopathy Neuroinflammation

1. Introduction

Sepsis is defined as a life-threatening organic dysfunction caused by a dysregulated host response to infection [1]. It was estimated that in 2017, there were 48.9 million cases and 11 million sepsis-related deaths worldwide, with a mortality rate that varies from 26% to 60% depending on the severity [2]. Despite all the efforts to improve sepsis treatment in the last decades, there is no specific therapy for sepsis, and mortality remains high, especially in low- and middle-income countries.
Sepsis is a clinical syndrome characterized by a maladaptive host response to infection that may be significantly amplified by endogenous factors. The pathogenesis of sepsis goes beyond an uncontrolled inflammatory response and includes major modifications in nonimmunologic systems such as cardiovascular, autonomic, neuroendocrine, coagulation, bioenergetic, and metabolic alterations [1]. While the inflammatory response in sepsis is relatively well-understood, the mechanisms driving metabolic deregulation and multiple organ dysfunction remain puzzling.
Multiple organ dysfunction is a hallmark of sepsis pathogenesis, and neurological manifestations are a frequent and underestimated symptom. Sepsis induces an acute brain dysfunction that is not related to direct brain infection and is characterized by various clinical and electroencephalographic changes [3][4]. This acute brain dysfunction is known as sepsis-associated encephalopathy (SAE), and it ranges from sickness behavior to altered consciousness, varying from confusion to delirium and, in worse cases, even coma [5]. SAE is strongly associated with higher mortality [6] and long-term cognitive impairments [7][8] affecting patients’ quality of life. To date, no curative or preventive treatment for SAE exists, and some pharmacological attempts have proved ineffective or even dangerous [9]. The absence of an effective therapeutic strategy is explained by the lack of precise knowledge of pathophysiological mechanisms. Some authors even suggest that the neurocognitive sequelae identified in the patients who had stayed in an ICU could be a risk factor for progressive neurodegenerative disorders of higher functions [10][11].
The mechanisms involved in SAE are diverse and include neurotransmitter dysfunction, inflammatory and ischemic lesions to the brain, microglia activation, changes in the blood–brain barrier (BBB) permeability, oxidative stress due to inflammation and mitochondrial dysfunction, and bioenergetic shifts that are part of metabolic adaptations to systemic inflammation [12][13]. Evidence suggests that alterations of the BBB resulting from both microglial and endothelial cell activation [14] could, in part, explain the acute neurological dysfunction by increasing the entry of inflammatory mediators and neurotoxic substances within the CNS [15]. Local production of pro-inflammatory markers and damage-associated molecular patterns (DAMPs) by the cells maintaining BBB (activated endothelial cells and astrocytes and perivascular macrophages) also contribute to neuroinflammation. Dysregulated cytokine responses are significant contributors to tissue injury and neurological deficits [16][17][18]. Inflammatory cytokines are involved in the pathophysiology of intensive care unit-acquired weakness, mostly, of neuropathies and myopathies [19]. All these mechanisms constitute a process known as neuroinflammation, which is the focus of this review.
To some extent, neuroinflammation is essential for maintaining brain homeostasis by inducing repair mechanisms. However, non-resolving neuroinflammation is a potentially harmful mechanism of brain damage. In this respect, microglia are major players in neuroinflammation, and exacerbated microglia activation has been associated with neurodegenerative diseases. As neurodegenerative diseases progress, microglia switch from a helpful role to a dysfunctional phenotype that becomes detrimental to neurons [20]. It is becoming clear that microglia surrounding Aβ plaques or Lewy bodies, for example, are not activated, but are nonfunctional [21]. There is a delicate balance determining whether microglia—and neuroinflammation in general—have beneficial or detrimental effects on the brain. This dual role is covered in the following sections, with a focus on sepsis and SAE.

2. Microglia in Sepsis-Associated Encephalopathy

Activated microglia exhibit rapid and profound morphological, phenotypic, bioenergetic, and functional changes in pathological conditions, broadly defined as “microglia activation” [22][23]. Microglia activation is a transient response characterized by an altered secretory profile, increased phagocytic activity, and deviation from the homeostatic phenotype.
Microglia activation is consistently observed acutely in sepsis, both in experimental models and septic patients [13][24]. Activated microglia express high levels of the 18-kDa translocator protein that can be measured in the human brain with the positron emission tomography (PET) radiotracer [11C] PBR28. LPS administration increased [11C] PBR28 binding, demonstrating microglia activation in human brains. This activation was associated with increased blood levels of inflammatory cytokines, vital sign changes, and sickness symptoms [25].
In a case-control study of 13 patients who died of sepsis, there was an increase in CD68 expression in the cortex compared to the control, and more amoeboid microglia were observed [26]. Similarly, in a postmortem case-control study of patients with delirium, there was an increase in microglial markers CD68 and HLA-DR compared to age-matched controls, suggesting that microglia activation could be related to delirium [27]. In a prospective study of 17 patients who died from septic shock, hippocampal tissue was assessed for a neuropathological study that observed increased microglia activation and apoptosis in septic patients with hyperglycemia [28].
The pathologic outcome of infections is a direct consequence of the extent of metabolic dysfunction and damage imposed on tissues that sustain host homeostasis [29]. Experimental models provide a deeper understanding of cellular response and the molecular mechanisms associated with organ dysfunction in sepsis. Oxidative stress and microglia activation have been consistently detected acutely in sepsis [12][24][30]. Genetic manipulation or pharmacological inhibition of pathways contributing to neuroinflammation and oxidative stress can protect survivors from neurocognitive impairments, indicating that neuroinflammation and oxidative stress are critical brain dysfunction mechanisms in SAE [31][32][33].

References

  1. Singer, M.; Deutschman, C.S.; Seymour, C.W.; Shankar-Hari, M.; Annane, D.; Bauer, M.; Bellomo, R.; Bernard, G.R.; Chiche, J.-D.; Coopersmith, C.M.; et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016, 315, 801.
  2. Rudd, K.E.; Johnson, S.C.; Agesa, K.M.; Shackelford, K.A.; Tsoi, D.; Kievlan, D.R.; Colombara, D.V.; Ikuta, K.S.; Kissoon, N.; Finfer, S.; et al. Global, Regional, and National Sepsis Incidence and Mortality, 1990–2017: Analysis for the Global Burden of Disease Study. Lancet 2020, 395, 200–211.
  3. Kafa, I.M.; Bakirci, S.; Uysal, M.; Kurt, M.A. Alterations in the Brain Electrical Activity in a Rat Model of Sepsis-Associated Encephalopathy. Brain Res. 2010, 1354, 217–226.
  4. Nielsen, R.M.; Urdanibia-Centelles, O.; Vedel-Larsen, E.; Thomsen, K.J.; Møller, K.; Olsen, K.S.; Lauritsen, A.Ø.; Eddelien, H.S.; Lauritzen, M.; Benedek, K. Continuous EEG Monitoring in a Consecutive Patient Cohort with Sepsis and Delirium. Neurocrit. Care 2020, 32, 121–130.
  5. Annane, D.; Sharshar, T. Cognitive Decline after Sepsis. Lancet Respir. Med. 2015, 3, 61–69.
  6. Ely, E.W. Delirium as a Predictor of Mortality in Mechanically Ventilated Patients in the Intensive Care Unit. JAMA 2004, 291, 1753.
  7. Eidelman, L.A. The Spectrum of Septic Encephalopathy. Definitions, Etiologies, and Mortalities. JAMA J. Am. Med. Assoc. 1996, 275, 470–473.
  8. Iwashyna, T.J.; Ely, E.W.; Smith, D.M.; Langa, K.M. Long-Term Cognitive Impairment and Functional Disability among Survivors of Severe Sepsis. JAMA 2010, 304, 1787.
  9. van Eijk, M.M.; Roes, K.C.B.; Honing, M.L.H.; Kuiper, M.A.; Karakus, A.; van der Jagt, M.; Spronk, P.E.; van Gool, W.A.; van der Mast, R.C.; Kesecioglu, J.; et al. Effect of Rivastigmine as an Adjunct to Usual Care with Haloperidol on Duration of Delirium and Mortality in Critically Ill Patients: A Multicentre, Double-Blind, Placebo-Controlled Randomised Trial. Lancet 2010, 376, 1829–1837.
  10. Perry, V.H.; Cunningham, C.; Holmes, C. Systemic Infections and Inflammation Affect Chronic Neurodegeneration. Nat. Rev. Immunol. 2007, 7, 161–167.
  11. Conde, J.R.; Streit, W.J. Effect of Aging on the Microglial Response to Peripheral Nerve Injury. Neurobiol. Aging 2006, 27, 1451–1461.
  12. Bozza, F.A.; D’Avila, J.C.; Ritter, C.; Sonneville, R.; Sharshar, T.; Dal-Pizzol, F. Bioenergetics, Mitochondrial Dysfunction, and Oxidative Stress in the Pathophysiology of Septic Encephalopathy. Shock 2013, 39, 10–16.
  13. Mazeraud, A.; Righy, C.; Bouchereau, E.; Benghanem, S.; Bozza, F.A.; Sharshar, T. Septic-Associated Encephalopathy: A Comprehensive Review. Neurotherapeutics 2020, 17, 392–403.
  14. van Gool, W.A.; van de Beek, D.; Eikelenboom, P. Systemic Infection and Delirium: When Cytokines and Acetylcholine Collide. Lancet 2010, 375, 773–775.
  15. Iacobone, E.; Bailly-Salin, J.; Polito, A.; Friedman, D.; Stevens, R.D.; Sharshar, T. Sepsis-Associated Encephalopathy and Its Differential Diagnosis. Crit. Care Med. 2009, 37, S331–S336.
  16. Dantzer, R.; O’Connor, J.C.; Freund, G.G.; Johnson, R.W.; Kelley, K.W. From Inflammation to Sickness and Depression: When the Immune System Subjugates the Brain. Nat. Rev. Neurosci. 2008, 9, 46–56.
  17. Kwon, A.; Kwak, B.O.; Kim, K.; Ha, J.; Kim, S.-J.; Bae, S.H.; Son, J.S.; Kim, S.-N.; Lee, R. Cytokine Levels in Febrile Seizure Patients: A Systematic Review and Meta-Analysis. Seizure 2018, 59, 5–10.
  18. Cook, A.D.; Christensen, A.D.; Tewari, D.; McMahon, S.B.; Hamilton, J.A. Immune Cytokines and Their Receptors in Inflammatory Pain. Trends Immunol. 2018, 39, 240–255.
  19. Friedrich, O.; Reid, M.B.; Van den Berghe, G.; Vanhorebeek, I.; Hermans, G.; Rich, M.M.; Larsson, L. The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill. Physiol. Rev. 2015, 95, 1025–1109.
  20. Aldana, B.I. Microglia-Specific Metabolic Changes in Neurodegeneration. J. Mol. Biol. 2019, 431, 1830–1842.
  21. Labzin, L.I.; Heneka, M.T.; Latz, E. Innate Immunity and Neurodegeneration. Annu. Rev. Med. 2018, 69, 437–449.
  22. Kettenmann, H.; Hanisch, U.-K.; Noda, M.; Verkhratsky, A. Physiology of Microglia. Physiol. Rev. 2011, 91, 461–553.
  23. Lauro, C.; Limatola, C. Metabolic Reprograming of Microglia in the Regulation of the Innate Inflammatory Response. Front. Immunol. 2020, 11, 493.
  24. Hoogland, I.C.M.; Houbolt, C.; van Westerloo, D.J.; van Gool, W.A.; van de Beek, D. Systemic Inflammation and Microglial Activation: Systematic Review of Animal Experiments. J. Neuroinflamm. 2015, 12, 114.
  25. Sandiego, C.M.; Gallezot, J.-D.; Pittman, B.; Nabulsi, N.; Lim, K.; Lin, S.-F.; Matuskey, D.; Lee, J.-Y.; O’Connor, K.C.; Huang, Y.; et al. Imaging Robust Microglial Activation after Lipopolysaccharide Administration in Humans with PET. Proc. Natl. Acad. Sci. USA 2015, 112, 12468–12473.
  26. Lemstra, A.W.; Groen in’t Woud, J.C.M.; Hoozemans, J.J.M.; van Haastert, E.S.; Rozemuller, A.J.M.; Eikelenboom, P.; van Gool, W.A. Microglia Activation in Sepsis: A Case-Control Study. J. Neuroinflamm. 2007, 4, 4.
  27. van Munster, B.C.; Aronica, E.; Zwinderman, A.H.; Eikelenboom, P.; Cunningham, C.; de Rooij, S.E.J.A. Neuroinflammation in Delirium: A Postmortem Case-Control Study. Rejuvenation Res. 2011, 14, 615–622.
  28. Polito, A.; Brouland, J.P.; Porcher, R.; Sonneville, R.; Siami, S.; Stevens, R.D.; Guidoux, C.; Maxime, V.; de la Grandmaison, G.L.; Chrétien, F.C.; et al. Hyperglycaemia and Apoptosis of Microglial Cells in Human Septic Shock. Crit. Care 2011.
  29. Kotas, M.E.; Medzhitov, R. Homeostasis, Inflammation, and Disease Susceptibility. Cell 2015, 160, 816–827.
  30. Towner, R.A.; Garteiser, P.; Bozza, F.; Smith, N.; Saunders, D.; D′Avila, J.C.P.; Magno, F.; Oliveira, M.F.; Ehrenshaft, M.; Lupu, F.; et al. In Vivo Detection of Free Radicals in Mouse Septic Encephalopathy Using Molecular MRI and Immuno-Spin Trapping. Free Radic. Biol. Med. 2013, 65, 828–837.
  31. Hernandes, M.S.; D’Avila, J.C.; Trevelin, S.C.; Reis, P.A.; Kinjo, E.R.; Lopes, L.R.; Castro-Faria-Neto, H.C.; Cunha, F.Q.; Britto, L.R.; Bozza, F.A. The Role of Nox2-Derived ROS in the Development of Cognitive Impairment after Sepsis. J. Neuroinflamm. 2014, 11, 36.
  32. Steckert, A.; Castro, A.; Quevedo, J.; Dal-Pizzol, F. Sepsis in the Central Nervous System and Antioxidant Strategies with Nacetylcysteine, Vitamins and Statins. Curr. Neurovasc. Res. 2014, 11, 83–90.
  33. Reis, P.A.; Alexandre, P.C.B.; D’Avila, J.C.; Siqueira, L.D.; Antunes, B.; Estato, V.; Tibiriça, E.V.; Verdonk, F.; Sharshar, T.; Chrétien, F.; et al. Statins Prevent Cognitive Impairment after Sepsis by Reverting Neuroinflammation, and Microcirculatory/Endothelial Dysfunction. Brain Behav. Immun. 2017, 60, 293–303.
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Joana D'Avila
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Update Date: 17 May 2021
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