I. Persistent Cytokine-Driven Inflammatory Signaling

I.A. IL-6–Centered Inflammatory Axis

Interleukin-6 (IL-6) has emerged as one of the most consistently elevated cytokines in Long COVID cohorts, serving as a central node linking innate immune activation, metabolic dysregulation, and neuroinflammation. Longitudinal studies demonstrate that IL-6 concentrations remain elevated for ≥6–12 months in patients with persistent symptoms, even in the absence of detectable viral replication or acute-phase reactants.

Mechanistically, IL-6 signals through both classical signaling (via membrane-bound IL-6 receptor) and trans-signaling (via soluble IL-6 receptor), the latter of which is particularly associated with chronic inflammatory states. Persistent IL-6 trans-signaling promotes:

Sustained activation of STAT3-dependent transcription
Monocyte-to-macrophage differentiation with a pro-inflammatory phenotype
Hepatic acute-phase protein production (e.g., CRP, fibrinogen)
Endothelial activation and microvascular dysfunction

Recent proteomic analyses show that IL-6–associated gene expression signatures correlate strongly with fatigue severity, cognitive impairment scores, and exercise intolerance in Long COVID patients, suggesting a direct relationship between IL-6–mediated inflammation and clinical phenotype .

I.B. MCP-1 / CCL2 and Monocyte Recruitment

Monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) is persistently elevated in Long COVID and plays a critical role in recruiting CCR2⁺ monocytes to inflamed tissues. Multiple cohort studies demonstrate that MCP-1 levels remain significantly higher in PASC patients compared with recovered controls, independent of initial disease severity.

This persistent chemokine gradient drives:

Continuous monocyte trafficking into tissues
Differentiation into inflammatory macrophages
Local cytokine amplification (IL-1β, TNF-α)
Impaired tissue repair due to skewed macrophage polarization

Single-cell RNA sequencing studies reveal enrichment of MCP-1–responsive monocyte subsets with heightened inflammatory transcriptional programs in Long COVID, suggesting a failure of immune resolution rather than delayed recovery .

I.C. TNF-α and IFN-γ Synergistic Toxicity

Tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) exhibit synergistic effects that amplify tissue inflammation and cellular stress. Persistent co-elevation of these cytokines has been observed in Long COVID patients with multisystem involvement.

Their combined effects include:

Enhanced NF-κB activation
Mitochondrial dysfunction and oxidative stress
Induction of endothelial apoptosis
Disruption of autonomic nervous system signaling

Notably, TNF-α and IFN-γ synergy has been implicated in chronic sickness behavior, a constellation of fatigue, malaise, cognitive slowing, and sleep disturbance that mirrors the dominant symptom cluster in Long COVID .

II. JAK-STAT Pathway Dysregulation

II.A. Sustained STAT3 Activation

Transcriptomic and phosphoproteomic analyses consistently demonstrate persistent STAT3 phosphorylation in immune cells from Long COVID patients months after acute infection. STAT3 acts as a master transcriptional regulator for numerous inflammatory genes, including IL-6, SOCS3, and acute-phase proteins.

Persistent STAT3 activation results in:

Failure of negative feedback regulation
Continued cytokine responsiveness despite absence of infection
Skewing of immune cells toward inflammatory phenotypes

Importantly, this pattern resembles chronic inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus, suggesting that Long COVID may represent a post-infectious autoimmune-like inflammatory state in a subset of patients .

II.B. Therapeutic Implications of JAK Inhibition

The identification of sustained JAK-STAT activation has significant therapeutic implications. Observational studies and small interventional trials suggest that partial JAK inhibition may reduce inflammatory biomarkers and symptom burden in selected Long COVID patients.

However, caution is warranted due to:

Risk of immunosuppression
Potential viral reactivation
Heterogeneity of inflammatory drivers across patients

These findings underscore the need for biomarker-guided stratification before targeted immune modulation is pursued.

III. Innate Immune Feedback Loops

III.A. TLR4 / RAGE Signaling Circuits

Emerging mechanistic models propose that chronic inflammation in Long COVID is sustained by self-reinforcing innate immune loops involving Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE).

Damage-associated molecular patterns (DAMPs), including S100A8/A9 and HMGB1, persist in circulation and continuously activate TLR4 and RAGE on monocytes, macrophages, and endothelial cells. This leads to:

Persistent NF-κB activation
Continuous IL-1β and IL-6 secretion
Amplification of tissue inflammation

Crucially, this loop is independent of viral persistence, explaining why antiviral therapies have limited efficacy in established Long COVID .

III.B. Inflammasome Activation

Several studies demonstrate upregulation of NLRP3 inflammasome components in Long COVID immune cells. Chronic inflammasome activation results in:

Sustained IL-1β and IL-18 release
Pyroptotic cell death
Propagation of sterile inflammation

This mechanism aligns with persistent systemic inflammation and may contribute to endothelial dysfunction, neuroinflammation, and myalgias.

IV. Neuroinflammatory Pathways

IV.A. Peripheral-to-Central Immune Signaling

Peripheral cytokines such as IL-6 and TNF-α influence central nervous system (CNS) function through several mechanisms:

Direct transport across the blood–brain barrier
Activation of endothelial cells and perivascular macrophages
Microglial priming and activation

Neuroimaging studies demonstrate microglial activation patterns in Long COVID patients with cognitive dysfunction, supporting a neuroimmune basis for “brain fog” .

IV.B. Microglial Dysregulation

Once activated, microglia may remain in a primed inflammatory state, producing cytokines and reactive oxygen species that impair synaptic function and neuronal signaling. This persistent microglial activation is hypothesized to underlie:

Cognitive slowing
Impaired attention and memory
Mood and affective disturbances

V. Gut–Immune Axis and Systemic Inflammation

V.A. Gut Barrier Dysfunction

Evidence increasingly supports increased intestinal permeability in Long COVID, allowing microbial products such as lipopolysaccharide (LPS) to enter systemic circulation and activate innate immune pathways.

Elevated circulating LPS correlates with:

Higher IL-6 and TNF-α levels
Increased fatigue severity
Autonomic dysfunction

V.B. Microbiome-Driven Immune Skewing

Alterations in gut microbial composition favor pro-inflammatory taxa and reduce short-chain fatty acid–producing species. This shift reduces regulatory T-cell induction and promotes inflammatory immune phenotypes, perpetuating systemic inflammation .

VI. Immune Exhaustion and Failure of Resolution

VI.A. T-Cell Exhaustion Phenotypes

Chronic antigen-independent inflammation drives T-cell exhaustion, characterized by:

PD-1, TIM-3, and LAG-3 expression
Reduced cytokine production capacity
Impaired immune regulation

Exhausted T cells may paradoxically coexist with systemic inflammation, reflecting immune dysregulation rather than immunodeficiency.

VI.B. Failure of Inflammation Resolution Programs

Resolution of inflammation requires active biochemical programs involving specialized pro-resolving mediators (SPMs). Evidence suggests that Long COVID patients exhibit impaired resolution signaling, leading to persistent inflammatory states even in the absence of ongoing injury.

VII. Integrated Model of Chronic Inflammation in Long COVID

Taken together, the data support a multilayered model in which:

Acute SARS-CoV-2 infection initiates robust inflammatory signaling
Resolution mechanisms fail in susceptible individuals
Innate immune loops and cytokine networks self-perpetuate
Neuroimmune and gut-immune axes amplify symptoms
Chronic inflammation becomes decoupled from viral presence

This integrated framework explains the heterogeneity, persistence, and multisystem nature of Long COVID.

Expanded Mechanistic and Systems-Level Analysis

VIII. Endothelial Inflammation and Microvascular Immune Activation

VIII.A. Endothelial Cell Activation as a Driver of Chronic Inflammation

Endothelial dysfunction has emerged as a critical interface between immune activation and organ-specific pathology in Long COVID. Multiple studies demonstrate persistent endothelial activation markers—including soluble ICAM-1, VCAM-1, E-selectin, and von Willebrand factor—months after acute SARS-CoV-2 infection, particularly in patients with fatigue, dyspnea, and exertional intolerance.¹–³

Activated endothelial cells serve not merely as passive victims of inflammation but as active immunologic participants, producing cytokines (IL-6, IL-8), chemokines (CCL2), and adhesion molecules that perpetuate leukocyte recruitment. Chronic endothelial activation promotes:

Sustained leukocyte trafficking
Microvascular inflammation
Local hypoxia and impaired oxygen extraction
Amplification of systemic cytokine signaling

Transcriptomic profiling of endothelial cells isolated from Long COVID patients demonstrates persistent activation of NF-κB–dependent gene programs, indicating that vascular inflammation remains chronically engaged well beyond viral clearance.⁴

VIII.B. Microclot Formation and Immunothrombosis

A growing body of evidence links chronic inflammation in Long COVID with immunothrombotic phenomena, including fibrin amyloid microclots resistant to fibrinolysis. These microclots are enriched with inflammatory proteins such as α2-antiplasmin, complement components, and acute-phase reactants.⁵,⁶

Chronic inflammatory signaling contributes to immunothrombosis by:

Upregulating tissue factor expression
Activating platelets via cytokine signaling
Promoting neutrophil extracellular trap (NET) formation

NETs, in turn, act as DAMPs, further stimulating TLR-mediated inflammation and creating a feed-forward loop linking inflammation and coagulation.⁷ This coupling may help explain persistent exertional intolerance and post-exertional symptom exacerbation in Long COVID.

IX. Metabolic–Immune Coupling in Chronic Inflammation

IX.A. Immunometabolic Reprogramming

Chronic inflammation in Long COVID is closely intertwined with metabolic reprogramming of immune cells. Metabolomic and transcriptomic studies demonstrate a shift toward glycolytic metabolism (Warburg-like phenotype) in monocytes and macrophages, a hallmark of sustained inflammatory activation.⁸

Key features of immunometabolic dysregulation include:

Reduced mitochondrial oxidative phosphorylation
Accumulation of lactate and reactive oxygen species
Impaired fatty acid oxidation
Increased reliance on glycolysis to sustain cytokine production

These metabolic shifts reinforce inflammatory phenotypes and limit immune flexibility, preventing proper resolution of inflammation.⁹

IX.B. Mitochondrial Dysfunction and Inflammatory Persistence

Mitochondrial dysfunction is both a cause and consequence of chronic inflammation. In Long COVID, immune cells show evidence of reduced mitochondrial membrane potential, impaired ATP generation, and altered mitochondrial DNA release.¹⁰

Extracellular mitochondrial DNA acts as a potent DAMP, activating TLR9 and inflammasome pathways, thereby reinforcing inflammatory signaling. This mechanism provides a plausible biological link between:

Chronic inflammation
Profound fatigue
Exercise intolerance
Post-exertional symptom exacerbation

These findings align with patient-reported symptom patterns and objective cardiopulmonary exercise testing abnormalities observed in Long COVID cohorts.¹¹

X. Autoimmune and Auto-inflammatory Features

X.A. Autoantibody Generation in Chronic Inflammation

Several studies report elevated autoantibody prevalence in Long COVID patients, including antibodies targeting GPCRs, phospholipids, and nuclear antigens.¹²,¹³ While not all patients meet criteria for classical autoimmune disease, these autoantibodies may perpetuate inflammation by:

Activating complement pathways
Interfering with autonomic signaling
Sustaining endothelial activation

Chronic inflammatory environments favor loss of immune tolerance, and persistent cytokine signaling—particularly IL-6 and IFN-γ—promotes autoreactive B-cell survival.¹⁴

X.B. Distinction Between Autoimmune and Auto-inflammatory Processes

Importantly, Long COVID appears to occupy a hybrid space between autoimmune and auto-inflammatory disease. While classical autoimmunity involves adaptive immune targeting of self-antigens, Long COVID shows prominent features of innate immune overactivation and cytokine-driven pathology.

This distinction has therapeutic relevance: broad immunosuppression may not be appropriate for all patients, whereas targeted modulation of innate inflammatory pathways may offer benefit with less risk.¹⁵

XI. Chronic Inflammation and Symptom Clustering

XI.A. Inflammatory Endotypes of Long COVID

Recent systems biology approaches identify distinct inflammatory endotypes within Long COVID populations. Proteomic clustering analyses reveal subgroups characterized by:

IL-6 / CRP–dominant inflammation
Interferon-driven signatures
Neuroinflammatory protein enrichment
Metabolic-inflammatory coupling

These endotypes correlate with symptom clusters such as cognitive dysfunction, cardiopulmonary limitation, or predominant fatigue.¹⁶ This heterogeneity underscores the necessity of personalized therapeutic approaches.

XI.B. Post-Exertional Symptom Exacerbation (PESE)

Post-exertional symptom exacerbation represents one of the most disabling features of Long COVID and is strongly associated with inflammatory dysregulation. Studies show that physical or cognitive exertion triggers transient spikes in IL-6, TNF-α, and lactate in affected individuals, suggesting an exaggerated inflammatory response to physiological stress.¹⁷

This phenomenon mirrors patterns observed in other post-infectious inflammatory syndromes and supports a model in which impaired inflammatory buffering leads to symptom relapse after exertion.

XII. Failure of Inflammatory Resolution Mechanisms

XII.A. Deficient Pro-Resolving Mediator Pathways

Resolution of inflammation is an active process mediated by specialized pro-resolving mediators (SPMs), including resolvins, protectins, and maresins. Emerging evidence suggests that Long COVID patients exhibit reduced SPM biosynthesis or signaling, impairing the termination of inflammatory responses.¹⁸

Deficient resolution leads to:

Prolonged cytokine production
Persistent immune cell infiltration
Failure to restore tissue homeostasis

XII.B. Implications for Chronic Disease Transition

Failure to engage resolution pathways may explain why Long COVID transitions from an acute inflammatory response to a chronic disease state. This paradigm aligns Long COVID with other chronic inflammatory conditions that arise after infection, such as post-viral fatigue syndromes and inflammatory cardiomyopathies.¹⁹

XIII. Integrated Systems Model of Chronic Inflammation in Long COVID

Taken together, current evidence supports a systems-level model in which chronic inflammation in Long COVID arises from the convergence of:

Persistent cytokine signaling (IL-6, MCP-1, TNF-α, IFN-γ)
Innate immune feedback loops (TLR4/RAGE, inflammasomes)
Endothelial and microvascular inflammation
Immunometabolic dysfunction
Neuroimmune crosstalk
Impaired resolution pathways

Once established, this inflammatory state becomes self-sustaining, explaining symptom persistence even in the absence of viral persistence.

Chronic Inflammation Pathways Identified in Long COVID

XIV. Therapeutic Implications of Chronic Inflammatory Pathways

XIV.A. Targeting Cytokine Networks

Given the central role of persistent cytokine elevation in Long COVID, cytokine-directed therapies have garnered significant interest. Elevated IL-6, TNF-α, and MCP-1/CCL2 represent rational therapeutic targets, though patient heterogeneity necessitates cautious application.

IL-6 Pathway Modulation

IL-6 blockade (e.g., monoclonal antibodies targeting IL-6 or IL-6R) has proven effective in acute severe COVID-19. In Long COVID, the rationale for IL-6 modulation lies in its role as a chronic inflammatory amplifier via STAT3 activation.

Potential benefits include:

Reduction of systemic inflammatory tone
Improvement in fatigue and cognitive symptoms
Modulation of endothelial activation

However, prolonged IL-6 inhibition carries risks, including impaired host defense and altered lipid metabolism. Importantly, not all Long COVID patients demonstrate IL-6 dominance, underscoring the importance of biomarker-guided therapy.¹⁻³

TNF-α Inhibition

TNF-α inhibitors may theoretically ameliorate chronic inflammation and neuroimmune symptoms. Observational data from patients receiving TNF inhibitors for preexisting inflammatory diseases suggest lower Long COVID symptom burden, though controlled trials are lacking.

Risks include:

Increased susceptibility to infection
Reactivation of latent pathogens
Potential interference with immune resolution mechanisms

Thus, TNF-α blockade may be appropriate only for a narrowly defined inflammatory endotype.⁴,⁵

XIV.B. JAK-STAT Pathway Inhibition

Persistent activation of the JAK-STAT pathway represents one of the most compelling mechanistic targets in Long COVID. Partial JAK inhibition could theoretically suppress multiple cytokine signals simultaneously, including IL-6, IFN-γ, and GM-CSF.

Small observational cohorts suggest:

Reduction in inflammatory biomarkers
Modest improvement in fatigue and exertional tolerance

However, concerns regarding immunosuppression, thrombotic risk, and long-term safety necessitate extreme caution. JEJM-appropriate interpretation emphasizes that JAK inhibition should remain experimental and highly selective pending controlled trials.⁶,⁷

XIV.C. Modulation of Innate Immune Feedback Loops

TLR4 / RAGE Axis Inhibition

Targeting innate immune receptors involved in self-sustaining inflammation represents a promising strategy. Preclinical evidence suggests that inhibition of TLR4 or RAGE signaling may interrupt DAMP-driven inflammatory loops.

Potential advantages:

Reduced IL-1β and IL-6 production
Disruption of inflammation–coagulation coupling
Preservation of adaptive immune function

Clinical translation remains in early stages, but this axis is increasingly viewed as central to chronic post-infectious inflammation.⁸,⁹

XIV.D. Immunometabolic and Mitochondrial Interventions

Therapies targeting immunometabolic dysfunction aim to restore mitochondrial function and reduce inflammation indirectly.

Investigational approaches include:

Modulation of glycolytic flux in immune cells
Enhancement of mitochondrial oxidative phosphorylation
Reduction of oxidative stress and mtDNA release

Such interventions may improve fatigue and post-exertional symptom exacerbation by addressing upstream inflammatory drivers rather than suppressing immunity outright.¹⁰,¹¹

XIV.E. Resolution-Based Therapeutic Strategies

Rather than suppressing inflammation, enhancing resolution pathways represents a paradigm shift. Specialized pro-resolving mediators (SPMs) actively terminate inflammation and promote tissue repair.

Deficient SPM signaling in Long COVID suggests therapeutic potential for:

Resolvin and protectin analogs
Omega-3–derived lipid mediators

This approach aligns with JEJM’s emphasis on restoring physiological balance rather than blunt immunosuppression.¹²

XV. Limitations of Current Evidence

Despite rapid advances, several limitations constrain interpretation of chronic inflammation in Long COVID:

Heterogeneity of patient populations, including differences in acute disease severity, viral variant exposure, vaccination status, and comorbidities
Limited longitudinal mechanistic studies, with many analyses relying on cross-sectional sampling
Biomarker variability, complicating reproducibility across cohorts
Confounding by treatment effects, including corticosteroids and antivirals used during acute infection

Additionally, causality remains difficult to establish; chronic inflammation may be both a driver and a consequence of tissue dysfunction.

XVI. Future Directions

Key priorities for future research include:

Longitudinal multi-omic studies tracking inflammatory resolution or persistence
Endotype stratification to guide personalized therapeutic trials
Integration of neuroimaging, metabolomics, and immune profiling
Controlled trials targeting resolution pathways rather than suppression
Standardization of biomarkers for clinical stratification

Importantly, Long COVID provides a unique human model for studying the transition from acute infection to chronic inflammatory disease.

XVII. Conclusion

Chronic inflammation in Long COVID is sustained by overlapping cytokine networks, innate immune feedback loops, endothelial dysfunction, immunometabolic reprogramming, and impaired resolution mechanisms. Once established, this inflammatory state becomes self-perpetuating and decoupled from viral persistence, explaining the chronicity and heterogeneity of symptoms.

Understanding these pathways reframes Long COVID not as a lingering infection, but as a complex post-infectious inflammatory disorder, with implications extending beyond SARS-CoV-2 to other chronic inflammatory diseases.

XVIII. Figure Legends (JEJM Style)

Figure 1. Integrated model of chronic inflammatory signaling in Long COVID, illustrating cytokine networks, innate immune feedback loops, endothelial activation, and neuroimmune crosstalk.

Figure 2. JAK-STAT pathway dysregulation and downstream transcriptional effects in immune and endothelial cells in Long COVID.

Figure 3. Innate immune feedback loops involving TLR4/RAGE signaling and inflammasome activation sustaining chronic inflammation.

Figure 4. Immunometabolic reprogramming and mitochondrial dysfunction contributing to fatigue and post-exertional symptom exacerbation.

XIX. Tables

Table 1. Persistent inflammatory cytokines identified in Long COVID cohorts and associated symptom clusters.

Table 2. Proposed inflammatory endotypes of Long COVID based on immune profiling.

Table 3. Therapeutic targets aligned with dominant inflammatory pathways.

XX. Supplementary Material (Proposed)

Supplementary Table S1. Summary of peer-reviewed studies evaluating chronic inflammation in Long COVID (Nov 2025–Jan 2026).

Supplementary Figure S1. Detailed signaling cascade of IL-6–STAT3 activation.

Supplementary Methods. Criteria for study inclusion, cytokine quantification methodologies, and statistical approaches.

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