RAGE–TLR4–NF-κB–CCL2 Looping Activation in Long COVID and Sensitization Syndromes

Dr Graham Exelby May 2025

Overview:

In Long COVID, POTS, and ME/CFS, chronic inflammation is sustained not by acute infection, but by maladaptive immune signalling loops. One of the key drivers of this persistent immune activation is the interplay between the Receptor for Advanced Glycation End Products (RAGE), Toll-Like Receptor 4 (TLR4), nuclear factor kappa B (NF-κB), and the chemokine CCL2. This loop amplifies neuroinflammation, endothelial dysfunction, and central sensitization.

Mechanism of Looping Activation:

• TLR4 and RAGE are pattern recognition receptors (PRRs) activated by danger signals (DAMPs) such as viral debris, oxidative stress byproducts, extracellular DNA, and advanced glycation end products.

• Activation of either receptor triggers NF-κB, a central inflammatory transcription factor.

• NF-κB induces expression of inflammatory cytokines (e.g., TNF-α, IL-6) and chemokines, most notably CCL2 (MCP-1).

• CCL2 recruits monocytes and microglia and further increases RAGE expression, sustaining the loop.- RAGE and TLR4 signalling also increase oxidative stress, endothelial leakiness, and mast cell priming.

Clinical Consequences of Looping Activation:

• Maintains a state of  low-grade chronic inflammation  despite absence of active infection.

• Sustains central sensitization (e.g., brain fog, allodynia, heat sensitivity).

• Impairs mitochondrial function via NF-κB-induced nitric oxide and reactive oxygen species.

• Contributes to vascular dysregulation, preload failure, and glymphatic suppression.

• Promotes neuroimmune crosstalk  involving mast cells, microglia, and astrocytes.

Targeted Therapies and Modulators:

• Low-dose naltrexone (LDN): Dampens microglial NF-κB signalling.

• Nicotinamide riboside: Supports mitochondrial resilience and SIRT pathway balance.

• Magnesium and B-complex: Support redox buffering and ATP synthesis.

• Telmisartan: Downregulates TLR4/NF-κB/CCL2 via AT1R and PPARγ.

• Quercetin: Inhibit mast cell–microglia signalling and NF-κB.

• Propranolol: Modulates IL-6, NF-κB, and limbic activation states.

Summary:

The RAGE–TLR4–NF-κB–CCL2 axis forms a self-reinforcing inflammatory circuit. In post-viral syndromes, this loop underlies chronic immune activation, central sensitization, and metabolic dysfunction. Breaking the loop requires upstream receptor modulation, mitochondrial support, and immune signal dampening.