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Dysregulated Resolution of Inflammation After Respiratory Viral Infections:: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by ELENA POPA.

Following respiratory viral infections, some individuals experience an incomplete resolution of inflammation, leading to prolonged activation of macrophages and microglia and the persistence of a neuroinflammatory environment. Mitochondrial dysfunction and oxidative stress further amplify pro-inflammatory signaling, while insufficient production of specialized pro-resolving mediators (such as resolvins and protectins) prevents the restoration of homeostasis. These interconnected processes can result in long-lasting neurological symptoms, including neuropathic pain, fatigue, and cognitive impairment.

  • viral infection
  • neuroinflammation
  • resolution of inflammation
  • neuropathic pain

1. Introduction

Inflammation is a fundamental innate immune response, essential for eliminating pathogens and harmful stimuli, as well as for restoring tissue homeostasis. Traditionally, the resolution of inflammation was considered a passive process, resulting from the dissipation of pro-inflammatory mediators [1,2,3][1][2][3]. However, recent research has demonstrated that resolution is an active, tightly regulated molecular and cellular process. It involves macrophage reprogramming through efferocytosis, post-transcriptional regulatory mechanisms, and the synthesis of specialized pro-resolving lipid mediators (SPMs), such as lipoxins, resolvins, protectins, and maresins [2,4][2][4]. These molecules promote the clearance of apoptotic cells and tissue debris, inhibit excessive neutrophil recruitment and facilitate the transition toward reparative macrophage phenotypes, thereby preventing the progression from acute to chronic inflammation [2].
In some individuals, dysregulation or delay of the resolution phase results in a state of persistent low-grade inflammation [3]. This maladaptive response extends beyond the respiratory tract, disrupting peripheral and central nervous system (CNS) homeostasis and fostering chronic neuroinflammation [5]. Respiratory viruses are of particular relevance in this context because they induce robust epithelial and innate immune activation in airways, leading to the release of cytokines, chemokines, and epithelial alarmins that disseminate systemically, disrupt blood–brain barrier integrity, and prime microglia [5]. These mechanisms have been documented after infections with influenza viruses, Epstein–Barr virus, and especially SARS-CoV-2 [5]. Given the ability of respiratory viruses to combine epithelial injury with systemic immune activation, blood–brain barrier disruption, and glial priming, they represent a uniquely powerful model for studying how unresolved inflammation progresses toward neuroinflammation and neuropathic pain (NP) [5,6][5][6].
 
Clinically, these pathways are increasingly recognized in the neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC), a neurological phenotype within the broader spectrum of long COVID and in other post-viral syndromes characterized by fatigue, cognitive dysfunction, anosmia, and NP [6].
These clinical patterns highlight the need to clarify the mechanisms sustaining persistent inflammation after respiratory viral infections. Understanding the molecular mechanisms that link impaired resolution of inflammation with post-viral NP is essential for identifying novel therapeutic targets and preventing long-term sequelae [5]. This review integrates mechanistic insights and clinical observations to provide a framework for addressing neuroinflammatory states after respiratory viral infections.
The discovery of these mechanisms has led to a paradigm shift from conventional anti-inflammatory strategies (such as corticosteroids, nonsteroidal anti-inflammatory drugs, or anti-cytokine therapies) [7] toward resolution-oriented therapies, termed resolution pharmacology [8]. These approaches not only suppress inflammation but also stimulate endogenous mechanisms that restore homeostasis, with the potential to provide superior or synergistic benefits compared to classical treatments.
Over the past decades, significant progress has been made in clarifying the phases of the acute inflammatory response and resolution: initiation of inflammation through the recognition of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), activation of antimicrobial mechanisms, suppression of pro-inflammatory mediators, active resolution through efferocytosis, and SPM production, followed by the post-resolution phase characterized by adaptive immune cell infiltration and the establishment of immune memory [2,3,9][2][3][9]. The current therapeutic gap in the management of infections is the absence of agents capable of reactivating inflammatory resolution, which has increased interest in SPMs such as lipoxins and resolvins [10]. Importantly, after respiratory viral infections, failure of this resolution process establishes a pathogenic trajectory from acute inflammation to chronic low-grade inflammation, neuroinflammation, and ultimately NP [5].
In this context, increasing attention has been directed toward biomarkers capable of capturing maladaptive innate immune activation and impaired inflammatory resolution following viral infections [5,8][5][8]. Biomarkers reflecting monocyte–macrophage activation—such as the soluble form of the CD14 receptor, including its proteolytic fragment presepsin (sCD14-ST)—reflect amplified pattern-recognition signaling, inefficient clearance of DAMPs and PAMPs and sustained innate immune activity [10]. These annormalities converge with reduced SPMs biosynthesis or receptor signaling, both of which are essential for promoting efferocytosis and terminating inflammatory responses. The combined imbalance between heightened pro-inflammatory signaling and insufficient resolution fosters a pro-inflammatory milieu conducive to persistent low-grade inflammation and increases susceptibility to neuroimmune dysregulation after respiratory viral infections [5,8][5][8].
Understanding these interconnected processes defines the mechanistic continuum from acute viral-induced inflammation to chronic neuroinflammatory and neuropathic states.

Integration of Mechanisms with Other Chronic Inflammatory Diseases

2. Integration of Mechanisms with Other Chronic Inflammatory Diseases

Post-viral neuropathic pain represents a paradigmatic example of disrupted inflammatory resolution following respiratory viral infection, illustrating the transition from a protective acute inflammatory response to a maladaptive chronic state [66][11]. The persistence of the neuroinflammatory microenvironment is sustained by an interconnected mechanism: inefficient efferocytosis and impaired clearance of apoptotic cells and tissue debris; continuous activation of macrophages, microglia, and astrocytes; reduced production of SPMs, required for terminating inflammation; and altered mitochondrial homeostasis, leading to excessive ROS generation and amplification of inflammatory stress [19,26,121][12][13][14]. These dysregulated processes sensitize central and peripheral nociceptive circuits and promote the development and maintenance of chronic NP [see Table 21]. Table 1. Specialized pro-resolving mediators (SPMs): biosynthesis, mechanisms, neuroinflammation/neuropathic pain, and post-viral relevance. 
SPM FamilyBiosynthesis and ReceptorsCore MechanismsNeuroinflammation/Neuropathic PainPost-Viral/COVID-19 Relevance
Lipoxins (LXA4, LXB4)Arachidonic acid via 15-LOX/5-LOX; main receptor ALX/FPR2 [15].Inhibits NLRP3, NF-κB, MAPK; lowers TNF-α/IL-1β/IL-6; supports epithelial repair [15].LXA4 reduces glial activation and neuropathic pain; ALX/FPR2 signaling dampens microglial reactivity; nano-LXA4 improves cognition in neurodegeneration (summarized from preclinical studies).ICU COVID-19 cohorts: low LXA4 despite severe disease; other SPMs rise but remain insufficient → impaired resolution [15][16].
Resolvins (RvD/E/T)From EPA/DHA via 5/12/15-LOX; aspirin-acetylated COX-2 yields AT-resolvins; receptors ChemR23, ALX/FPR2, GPR32 [15].Reduce neutrophil chemotaxis; increase phagocytosis/efferocytosis; lower IL-1β/IL-6/TNF-α; promote M2 polarization [15].Limit microglial/astrocytic activation; constrain inflammasome; protect cognition in models (overview and synthesis).Severe COVID-19: altered SPM profiles (↑RvE1, MaR2, RvD5; low LXA4), still inadequate resolution—candidate biomarkers/targets [15].
Protectins (PD1/NPD1/PDX)DHA-derived (15-LOX); receptors include ALX/FPR2 [9].Decrease oxidative stress and mitochondrial apoptosis; increase Iduna (DNA repair); stabilize BBB; promote neuro/angiogenesis [9].PD1n-3 DPA lowers hippocampal IL-1β/TNF-α and reduces seizures; ALX/FPR2 and ChemR23 upregulated in epileptogenic astrocytes [17].RSV: PCTR1/PD1 reduce viral load and lung inflammation, restore IFN-λ, induce cathelicidin [18]). COVID-19: higher plasma PD1 in critical illness associated with M2 polarization/IL-10 [19].
Maresins (MaR1/MaR2/MCTR)DHA → 12-LOX in macrophages; receptors LGR6, ALX/FPR2 [20][21].Enhance efferocytosis and tissue-repair programs; limit neutrophil influx/cytokines; MCTR couple clearance with regeneration [20][21].MaR1 mitigates perioperative neuroinflammation/cognitive decline [22]; promotes axonal regrowth; dampens spinal glia and TRPV1/PI3K-AKT-mTOR [23]; provides long-lasting analgesia via NF-κB/CGRP control [24]. MaR2 (intrathecal) reduces orofacial nociception, prevents postoperative hyperalgesia, and reverses trigeminal NP by suppressing c-Fos and NF-κB+/CGRP+ TG neurons [25].Post-COVID syndrome: 12-week SPM-enriched marine oil increased 14-HDHA/17-HDHA/18-HEPE and improved fatigue/dyspnea—supporting translational potential [26].
Abbreviations: LOX, lipoxygenase; COX-2, cyclooxygenase-2; BBB, blood–brain barrier; TG, trigeminal ganglion.
A similar same pathogenic pattern—defined by failure to efficiently resolve inflammation and restore immune-neuronal homeostasis—is observed across multiple chronic inflammatory disorders. In neurodegeneration, such as Alzheimer’s disease [122][27], microglia persist in a pro-inflammatory phenotype characterized by sustained IL-1β, TNF-α, and ROS secretion, while deficiencies in TREM2 and Gas6–Axl signaling impair the clearance of β-amyloid and synaptic debris, thereby perpetuating neuroinflammation and cognitive decline [36,123][28][29]. Wanke et al. (2021) [54][30] demonstrated that MERTK kinase activity is indispensable for efferocytosis in both murine and human macrophages, underscoring its conserved role as a molecular checkpoint for inflammation resolution. Defective of MERTK signaling leads to the accumulation of apoptotic cell, secondary necrosis, and amplification of pro-inflammatory cascades. Comparable alterations are present in autoimmune diseases. In systemic lupus erythematosus, defective apoptotic clearance results to persistent exposure to nuclear autoantigens, activation of the adaptive immune system, and chronic systemic inflammation [124][31]. In rheumatoid arthritis, synoviocytes and macrophages maintain a chronic pro-inflammatory profile, sustained by IL-6 and TNF-α, inhibiting repair and promoting joint destruction [125][32]. Marchand et al. (2023) [125][32] reported that RA patients display altered circulating profiles of SPM precursors, while fish-oil supplementation increases EPA- and DHA-derived SPM intermediates, suggesting that endogenous resolution pathways are impaired, but can be pharmacologically restored. Similarly, in osteoarthritis, impaired mitochondrial homeostasis and oxidative stress contributes to persistence of pain, whereas dimethyl fumarate improves mitochondrial biogenesis via Nrf2 activation and alleviated pain behaviors in experimental models [126][33]. Multiple sclerosis also features defective efferocytosis of degenerated myelin and NLRP3 inflammasome activation, sustaining CNS inflammation, contributing to progressive demyelination and neurodegeneration. Lipidomic analyses confirm that MS patients exhibit reduced levels of pro-resolving mediators (LXA4, RvD1, and PD1), correlating with disease severity, indicating systemic failure of resolution programs [127][34]. Importantly, beyond innate immunity, SPMs also regulate adaptive immune response. They promote macrophage polarization toward a pro-resolving M2 phenotype, restore efferocytosis, and limit inflammasome activation. In parallel, they regulate B-cell maturation and antibody production, acting as immune adjuvants or suppressors depending on the immunological context [124][31]. Such evidence reinforces the concept that impaired resolution is not only a feature of local tissue inflammation, but reflects a systemic immunoregulatory dysfunction shared across chronic diseases [124,127,128][31][34][35]. Therefore, the mechanisms described in post-viral NP should not be regarded as isolated phenomena, but rather as part of a broader spectrum of shared inflammatory dysregulation. This convergence underscores unresolved inflammation as a central pathogenic hub linking post-viral syndromes with chronic inflammatory disorders. Crucially, these parallels open translational therapeutic opportunities, suggesting that strategies aimed at restoring inflammation resolution—by enhancing efferocytosis, modulating SPM signaling, or targeting redox homeostasis—may hold promise across multiple disease contexts [8,75,124,127][8][15][31][34].
 
 
 
 
 
 
 
 

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