Dr Graham Exelby December 2024
Abstract
Central sensitization, characterized by increased responsiveness of the central nervous system (CNS) to sensory inputs, manifests clinically in symptoms such as widespread pain, fatigue, cognitive difficulties (commonly referred to as "brain fog"), and autonomic disturbances like orthostatic intolerance in POTS, Long COVID, and Fibromyalgia. It results from persistent neuroimmune activation, inflammatory signalling, and autonomic dysregulation.
The TLR4/RAGE pathway, amplified by damage-associated molecular patterns (DAMPs) and the SARS-CoV-2 spike protein, drives NF-κB activation and cytokine release (IL-6, TNF-α, IL-1β). Understanding this pathway enables clinicians to identify potential therapeutic targets, such as TLR4 antagonists or NF-κB inhibitors, which could modulate the inflammatory cascade.
Additionally, CCL2 (monocyte chemoattractant protein-1) perpetuates neuroinflammation via microglial activation, creating a self-sustaining inflammatory feedback loop. These mechanisms result in widespread pain, fatigue, and autonomic dysfunction, hallmarks of these chronic conditions.
Introduction to Central Sensitization
Central sensitization refers to an increased central nervous system (CNS) responsiveness to peripheral inputs, driven by chronic inflammation, microglial activation, and neurotransmitter dysregulation. Originally described in fibromyalgia, central sensitization now explains overlapping mechanisms in POTS, Long COVID, and Gulf War Syndrome (GWS).
Persistent immune activation and neuroinflammation amplify neuronal excitability, lowering the threshold for pain perception and autonomic dysfunction. Clinically, these mechanisms contribute to challenges in diagnosing overlapping syndromes due to shared symptoms like chronic pain, fatigue, and autonomic instability. They also complicate treatment strategies, as effective management requires addressing both peripheral triggers and central sensitization processes.
Understanding the complexity of conditions like POTS, Long COVID, and fibromyalgia requires a comprehensive evaluation of underlying causes and comorbidities unique to each patient. Each case is influenced by a distinct combination of “activators”—factors that initiate immune and inflammatory cascades—and “drivers”, which perpetuate these processes. These activators can range from infections, trauma, and surgery to sustained stress, pregnancy, or mechanical dysfunctions.
In COVID-triggered POTS, for example, immune dysregulation is particularly complex due to a mix of autonomic instability and thrombo-inflammatory processes. However, similar mechanisms can follow other triggers, such as parasites (e.g., Blastocystis hominis), sustained stress, PTSD, or upper cervical spine trauma.
Lessons learned from COVID have greatly advanced our understanding of POTS and its diverse causes, highlighting the need to identify and manage the underlying activators for effective treatment. Therapeutically, insights into TLR4/NF-κB inhibition have inspired trials of repurposed drugs like famotidine and experimental TLR4 antagonists to mitigate inflammation and autonomic dysregulation.
Table 1. Common Activators of POTS and Central Sensitization
These are detailed, with the ongoing drivers in
Viral infections (e.g., COVID-19)
Trauma (upper cervical spine, coccyx, thoracic outlet injury)
Parasitic infections (e.g., Blastocystis hominis, H. pylori)
Sustained stress and PTSD
Pregnancy
Surgical procedures
Prolonged mechanical strain (e.g., backpack/camera use)
Environmental exposures (mould, chemicals)
Sensitization Mechanisms
Peripheral sensitization arises from hyperresponsive nociceptors (sensory receptors) triggered by inflammation, immune activation, or tissue injury. This lowers the activation threshold and amplifies peripheral pain signals. Chronic peripheral input drives central sensitization, where prolonged activation of spinal and brain pathways induces hyperexcitability of CNS pain-processing neurons.
In the CNS, microglial activation amplifies neuroinflammation by releasing pro-inflammatory cytokines (e.g., TNF-α, IL-6), while reactive astrocytes impair glymphatic clearance, causing the accumulation of neurotoxic substances like glutamate. This creates a self-sustaining feedback loop of pain amplification, fatigue, and autonomic dysfunction characteristic of POTS, Long COVID, and fibromyalgia.
Key Molecular Mechanisms of Central Sensitization:
Toll-Like Receptor 4 (TLR4) Activation: Persistent activation by damage-associated molecular patterns (DAMPs) or viral remnants triggers NF-κB signalling, which correlates with chronic inflammation observed in conditions like Long COVID and manifests as widespread pain and fatigue in patients.
Cytokine Release: Pro-inflammatory mediators (IL-1β, IL-6, TNF-α) amplify neuroinflammation and disrupt CNS-PNS communication.
CCL2 and RAGE Activation: Chemokine release recruits immune cells, sustaining neuroinflammation through feed-forward loops.
Astrocyte-Glutamate Dysregulation: TLR2 signalling impairs astrocytic glutamate clearance, contributing to excitotoxicity and heightened neuronal sensitivity.
Figure 1. Mast Cell, Microglia and Astrocyte Cross-Talk
Source: Carthy, Elliott & Ellender, Tommas. (2021). Histamine, Neuroinflammation and Neurodevelopment: A Review. Frontiers in Neuroscience. 15. 10.3389/fnins.2021.680214.(17)
Conclusion
Central sensitization in POTS, Long COVID, and fibromyalgia arises from a multifactorial interplay involving immune activation, neuroinflammation, and mechanical dysfunctions. Understanding the molecular drivers, such as TLR4/NF-κB activation, cytokine overactivity, and microglial-astrocyte crosstalk, offers insights into disease mechanisms and potential therapeutic targets.
By identifying and addressing the specific activators and drivers in each patient, clinicians can disrupt the sensitization cascade, ultimately improving patient management and outcomes. For instance, therapies like low-dose naltrexone (LDN) have shown promise in modulating neuroinflammation, while lifestyle interventions targeting stress reduction and physical therapy address autonomic and mechanical dysfunctions. These approaches complement pharmacological treatments targeting pathways such as TLR4 and NF-κB.
The SARS-CoV-2 Infection and the Inflammatory Pathways- understanding the involved pathways
SARS-CoV-2 Entry and Initial Immune Response
SARS‐CoV‐2 enters the body and its spike (S) protein interacts with ACE2 receptors to infect respiratory epithelial and immune cells. During infection, rapid viral replication causes a strong immune response and immune dysregulation.(1)
At the early stage, the virus infects the lung epithelial cells and is slowly transmitted to the other organs including the gastrointestinal tract, blood vessels, kidneys, heart, and brain. The neurological effect of the virus is mainly due to hypoxia‐driven reactive oxygen species (ROS) and generated cytokine storm.
Cytokine Storm and Hypercoagulability
Internalization of SARS‐CoV‐2 triggers ROS production and modulation of the immunological cascade which ultimately initiates the hypercoagulable state and vascular thrombosis. (2) Immune cells are extensively activated and secrete large amounts of inflammatory factors, causing excessive inflammation and the “cytokine storm,” which can lead to immunopathological impairment of COVID‐19, closely related to the severity of the disease. (1)
The hypercoagulability with alterations in haemostatic markers including high D-dimer levels, together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, reveals COVID-19 to be a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19.(3)
Neurological Effects and Neuroinflammation
Sashindranath and Nandurkar (3) described an established link between COVID-19 and neurological symptoms in up to 50% of patients.
Neurological Complications: Loss of smell/taste, encephalitis, seizures, Guillain-Barré syndrome, and cognitive dysfunction (3)
Vascular Complications: Hypercoagulability, microthrombi, cerebrovascular disease, and BBB disruption.(3)
Acute cerebrovascular disease with a relatively low mean age (ranging from 45 to 67 years) is a significant complication of COVID-19. “That the overall incidence of large vessel occlusions is 2-fold higher than in normal acute ischaemic stroke cases and they occur among patients from all age groups, even those without risk factors or comorbidities, strongly implicates COVID-19-related hypercoagulability as the underlying cause.
The endothelium has a pivotal role in cerebrovascular disease. Endothelial dysfunction occurs after stroke and leads to oxidative stress, inflammation, increased vascular tone, blood-brain barrier (BBB) damage, and further thrombovascular complications in the brain.”(3)
The pathophysiology of COVID-19 is characterized by systemic inflammation, hypoxia resulting from respiratory failure, and neuroinflammation (either due to viral neurotropism, the ability of the virus to invade and live in neural tissue, or in response to the cytokine storm), all affecting the brain. (4)
The brain and spinal cord, which make up the CNS, are not usually accessed directly by pathogenic factors in the body's circulation due to a series of endothelial cells (single layer of squamous cells that form an interface between circulating blood or lymph in the vessels, controlling the flow of substances into and out of a tissue) known as the blood -brain barrier (BBB) (formed from endothelial cells, astrocyte end-feet and pericytes.)
The BBB prevents most infections from reaching the vulnerable nervous tissue. In the case where infectious agents are directly introduced to the brain or cross the blood–brain barrier, microglial cells must react quickly to decrease inflammation and destroy the infectious agents before they damage the sensitive neural tissue, so basically are the “first responders” in infections.
Role of TLR Signaling in COVID-19 Pathogenesis
In humans there are 10 types of body threat receptors, or Toll-Like Receptors (TLRs) that respond to a variety of PAMPs (pathogen-associated molecular patterns associated with bacteria and viruses), and DAMPS (damage-associated molecular patterns). TLRs are crucial components in the initiation of the innate immune system, triggering the downstream production of pro-inflammatory cytokines, interferons (IFNs) and other mediators. TLRs recognize invading pathogens by sensing PAMP and DAMP and activate the regulation of innate immunity and cytokines. TLR activation leads to the production of proinflammatory cytokines and Interferon IFN.(4)
TLRs 1,2,4,5,6,10 are plasma protein TLRs, while TLR3 and 7 are on endosomes (intracellular sorting organelles). TLR2/6 and TLR4 are located on the cell membrane. TLR2 senses the SARS-CoV-2 envelope protein (E), resulting in production of inflammatory cytokines and chemokines, contributing to the hyperinflammatory state and tissue damage seen in severe Covid. The severity of the Covid infection is largely determined by the E Protein /TLR2 activation rather than the S protein.(4)(5)
TLR4 signalling is activated by the Spike protein (S). This can lead to a pro-thrombotic and pro-inflammatory state contributing to severe complications eg myocardial infarction and acute lung injury.(6)(7) It is also responsible for other symptoms such as neuropathy.
While TLR2 activation (via the SARS-CoV-2 envelope protein) amplifies cytokine production and contributes to tissue damage, TLR4 activation (via the spike protein) promotes both pro-thrombotic and inflammatory states, leading to vascular complications and neuropathy.
Figure 2. Downstream Signalling Pathways of TLRs
Source: Mantovani S, Oliviero B, Varchetta S, Renieri A, Mondelli MU. TLRs: Innate Immune Sentries against SARS-CoV-2 Infection. Int J Mol Sci. 2023 (4)
The endosomal TLR3 senses intracellular viral dsRNA. Activated TLR regulates the production of proinflammatory factors through a series of signalling in the NF‐κB pathway and activates IRF3/7 to produce Interferon 1, (I IFN) cytokines that play essential roles in inflammation, immunoregulation, tumour cell recognition and T-cell responses. (8)(9) A DNA variant in TLR3 has also been identified as increasing susceptibility and mortality to acute COVID infections by decreasing TLR3 expression and impairing recognition of SARS-Co-V dsRNA. (4) These results suggest perivascular inflammation may be a critical factor in Long COVID.
Microglial and Astrocyte Activation
Damage to the brain triggers a specific type of reactive response mounted by neuroglia cells, in particular by microglia, the most prominent immune cells in the CNS and which are the first to respond to threat.(10) Inflammatory microglial activation (IL-6 and TNFa) is the most common brain pathology found in patients who died of COVID-19: 42% are affected, and another 15% have microclots in brain tissue.(10)
Microglia, the resident immune cells in the brain, play an important role in brain inflammation, while brain mast cells, rather than microglia, are the "first responders" to the injury to the brain. The complex nature of the immune response and mast cell activation in now an integral part of Long Covid pathogenesis.(11)
COVID reduces the morphology and distribution of microglia and astrocytes in the hippocampus which has a major role in learning and memory. Mast cells promote cross-talk between T cells and myeloid cells like microglia during neuroinflammation, and the complex interplay between the activated microglia, reactive astrocytes and mast cells is a key part of the neurological manifestations of the COVID-19 infection.(12)(13(14) (Figure 1)
Astrocytes are the primary targets of SARS-CoV-2 in the brain, and SARS-CoV-2 preferentially infects and replicates and propagates in astrocytes, particularly those adjacent to infected vasculature. In contrast, neurons and microglia are less likely to be directly infected. Importantly, while microglia and astrocytes are both reactivated, a direct dosage-sensitive effect of SARS-CoV-2 is only observed in reactive astrocytes. SARS-Co-V preferentially infects astrocytes over neurons resulting in astrocyte reactivation and neuronal death (10).
This is complicated by astrocyte/ microglial “cross-talk” and neurotransmitter dysregulation. The SARS-Co-V spike protein activates microglia leading to pro-inflammatory effects and microglial-mediated synapse elimination. This microglial activation and neuroinflammation can disrupt the BBB.
Microglia:
Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord that 10% to 15% of all cells found within the brain. Clough et al (15) describe: “Microglia are the resident immune cells of the Central Nervous System (CNS). Microglia have the capacity to migrate, proliferate and phagocytize. Under physiological conditions, microglia exist in their “resting” state, however on exposure to a pathogen, microglia transition into an activated state and quickly mobilize to the site of injury to initiate an innate immune response.” They are the first and main form of active immune defense in the central nervous system- on exposure to pathogen, activated and mobilize to injury site.
They are crucial for the formation, shaping, and functioning of synapses, fundamental for brain development during pre- and post-natal periods. (10) Astrocyte/microglial crosstalk with mast cells as a critical component of the immune response- (Figure 1)
Astrocytes:
Astrocytes are the most abundant glial cells in the CNS. They maintain CNS homeostasis, including neurotransmitter regulation, particularly glutamate where in COVID astrocyte reactivity and subsequent glutamate dysregulation contributes to neurological symptoms eg cognitive impairment, fatigue and mood disorders.
Blood flow in the brain is regulated by neurons and astrocytes. Attwell et al (16) describe “It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles.” Astrocytes can promote the induction and progression of inflammatory states, which are significantly associated with the disease status or severity.
Astrocytes, with their end feet enveloping the cerebral blood vessels, play a pivotal role in glymphatic function, facilitating the exchange between cerebrospinal fluid (CSF) and interstitial fluid (ISF) alongside perivascular spaces.
Activation of TLR2, the other immune system “first responder” appears to affect the astrocytes. The astrocytes form the paravascular spaces thus dysfunction in the astrocytes can affect the glymphatic system function (reducing toxin clearance from the brain.) It is proposed that cerebrospinal fluid enters the brain via paravascular spaces along arteries, mixes with interstitial fluid, and leaves via paravascular spaces along veins. This flow is disrupted by the astrocyte damage in COVID.
The intricate interplay between SARS-CoV-2, TLR signalling, and immune activation drives systemic inflammation, hypercoagulability, and neuroinflammation. Astrocyte dysfunction, microglial activation, and BBB disruption underlie the neurological manifestations of COVID-19, contributing to both acute and long-term complications such as cognitive dysfunction, fatigue, and persistent neuroimmune dysregulation observed in Long COVID.
Critical Elements in Immune Dysfunction
NFkB (Nuclear factor kappa-light-chain-enhancer of activated B cells)
NFkB is a protein complex that plays a crucial role in regulating the immune response, inflammation, and cell survival. The primary function of NFkB is to control gene expression in response to various signals, such as pro-inflammatory cytokines, bacterial or viral products, stress, and oxidative damage. In its inactive state, NFkB is located in the cytoplasm, where it is bound to its inhibitory proteins (IκBs). Upon activation by a stimulus, IκBs are phosphorylated and degraded, releasing NFkB to translocate to the nucleus. In the nucleus, NFKB binds to specific DNA sequences called κB sites and regulates the transcription of target genes involved in inflammation, immune response, cell survival, and apoptosis.
NFkB activation is tightly regulated to prevent excessive or prolonged inflammation, which can lead to tissue damage and chronic diseases. Dysregulation of NFkB signalling has been implicated in various health conditions, including autoimmune disorders, inflammatory diseases, cancer, and neurodegenerative diseases.
CCL2 (monocyte chemoattractant protein-1)
CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), is a chemokine (cytokine or signalling protein that induces cell migration, especially leucocytes) that is involved in the recruitment and activation of monocytes and other immune cells. It helps guide immune cells towards tissue injury and inflammation, and stimulates superoxide and further expression of pro-inflammatory genes.
CCL2 has been identified as a mediator that can be released by activated mast cells, and elevated levels of CCL2 have been found in the serum of patients with MCAS. CCL2 is a potent activator of mast cells, which are implicated in many, possibly all POTS patients. Mast cell degranulation releases histamine and other mediators, exacerbating vasodilation and vascular permeability, tachycardia and orthostatic symptoms.
Elevated levels of CCL2 have been implicated in various inflammatory conditions, including those affecting the nervous system with greater deficits in cognitive function, aberrant behaviour and Impaired development.(18)(19(20) Dysregulation of CCL2 expression has been implicated in the pathogenesis of various health conditions, including rheumatoid arthritis (25), IBS (26), fibromyalgia (21), chronic fatigue (22), chronic pain syndromes (23), POTS, connective tissue disease (24), ADHD (25), autism (26)(27). The involvement of CCL2 in inflammatory processes and its dysregulation in various autoimmune and chronic conditions suggest that it may play a role in MCAS, breast cancer, POTS and pelvic congestion.
By binding to CCR2 receptors on sensory neurons in the dorsal root ganglia (DRG), CCL2 amplifies nociceptive signalling and autonomic dysfunction, underpinning symptoms like tachycardia, fatigue, and widespread pain in POTS and Long COVID.
The activation of TLR4/NF-κB signaling not only initiates the inflammatory cascade but also induces the expression of chemokines like CCL2, which perpetuate inflammation and central sensitization.
Postural orthostatic hypertension (POTS): CCL2 has been found to be elevated in the serum of patients with POTS, suggesting a role for CCL2 in the autonomic dysfunction associated with this condition.
Chronic CCL2-mediated inflammation may contribute to sensitize adrenergic receptors, leading to sympathetic overactivity. This manifests as exaggerated tachycardia and other autonomic symptoms upon standing.
CCL2 has also been associated with vascular dysregulation and endothelial dysfunction (28) and is thought may contribute to the disruption of the blood-brain barrier (29)
Elevated CCL2 levels are thought to perpetuate local inflammation and fibroblast activity, leading to collagen and fascia remodelling that impairs lymphatic drainage and contributes to persistent compression.
CCL2 expression is hypothesized to be associated with other vascular compression syndromes (e.g., May-Thurner, Nutcracker). CCL2 promotes the recruitment of inflammatory cells, which could lead to local inflammation in compressed areas.
Elevated CCL2 levels may stimulate fibroblast activity and collagen production, potentially contributing to fascial changes.(30)
Mast cell activation syndrome (MCAS): CCL2 has been identified as a mediator that can be released by activated mast cells, and elevated levels of CCL2 have been found in the serum of patients with MCAS. CCL2 is a potent activator of mast cells, which are implicated in many POTS patients. Mast cell degranulation releases histamine and other mediators, exacerbating vasodilation and vascular permeability, tachycardia and orthostatic symptoms.
Elevated CCL2 can disrupt the function of the NTS and PVN, critical brainstem regions involved in autonomic regulation. CCL2 and its receptor CCR2 are expressed in central autonomic control centres like the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM.) (29) This can result in altered sympathetic outflow to cardiovascular organs, changes in blood pressure regulation and disruption of respiratory control.(37)(38)
Fibromyalgia: Some studies have suggested that CCL2 may play a role in the pathogenesis of fibromyalgia, as elevated levels of CCL2 have been found in the cerebrospinal fluid of patients with fibromyalgia.(21)
Connective tissue disease: CCL2 has been implicated in the pathogenesis of connective tissue diseases, including systemic sclerosis and rheumatoid arthritis.
Breast cancer: CCL2 has been implicated in the growth and spread of breast cancer cells, and high levels of CCL2 have been associated with a poor prognosis.(31)
Migraine with aura: CCL2 has been implicated in the inflammation and pain associated with migraine headaches, including those with aura.
Chronic fatigue: Elevated levels of CCL2 have been found in the serum of patients with chronic fatigue syndrome (CFS), suggesting a role for CCL2 in the pathogenesis of this condition.(32)
Chronic pain: CCL2 has been implicated in the pathogenesis of chronic pain, and elevated levels of CCL2 have been found in the serum and cerebrospinal fluid of patients with chronic pain conditions.(23)
Pelvic congestion: CCL2 has been implicated in the pathogenesis of pelvic congestion syndrome, a condition characterized by chronic pelvic pain.
Retrograde ovarian flow: CCL2 has been implicated in the pathogenesis of retrograde ovarian flow, a condition in which the menstrual blood flows backward into the abdomen instead of out of the body.
MALs (median arcuate ligament syndrome): CCL2 has been found to be elevated in the serum of patients with MALs, a condition characterized by chronic abdominal pain.
TOC (transverse ovarian vein compression syndrome): CCL2 has been found to be elevated in the serum of patients with TOC, a condition in which the ovarian vein is compressed, leading to pelvic pain.
IBS: There is some evidence that CCL2 may be involved in the inflammation and pain associated with irritable bowel syndrome (IBS). Elevated levels of CCL2 have been found in the intestinal mucosa of patients with IBS.
Hypertension: CCL2 has been found to be elevated in the serum of patients with hypertension, and has been implicated in the pathogenesis of hypertension.
Raynaud’s: CCL2 has been implicated in the pathogenesis of Raynaud's phenomenon, a condition characterized by constriction of the blood vessels in the fingers and toes in response to cold or stress.
Targeting key nodes in the TLR4/NF-κB/CCL2 pathway—such as using TLR4 antagonists, NF-κB inhibitors, or CCR2 blockers—represents a promising therapeutic approach for mitigating neuroinflammation, central sensitization, and chronic symptoms in conditions like Long COVID and POTS.
CCL2 activity may be modulated by H2 blocker famotidine (33) and mast cell stabilizer cromolyn.(34) Supplements thought to be of benefit include:
· Omega-3 fatty acids
· Curcumin
· Green tea
· Vitamin D
· Nigella sativa
· NAC
Persistent activation of the TLR4/NF-κB/CCL2 signalling axis underpins chronic neuroinflammation, glial activation, and sensory neuron sensitization. This pathway plays a central role in the pathophysiology of Long COVID, POTS, and other chronic pain syndromes, highlighting its potential as a therapeutic target to disrupt the cycle of inflammation and central sensitization.
Inflammasome
The NLRP3 inflammasome is a key component of the innate immune system and is activated in response to various danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). These stimuli include viral infections (e.g., SARS-CoV-2), asbestos, mitochondrial reactive oxygen species (ROS), extracellular ATP, and other cellular stress signals. The inflammasome acts as a multiprotein complex, primarily composed of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD), and caspase-1.
Upon activation, the NLRP3 inflammasome triggers the cleavage of pro-caspase-1 into its active form. This leads to the maturation and release of pro-inflammatory cytokines IL-1β and IL-18, both of which play central roles in amplifying the inflammatory cascade. In severe COVID-19, this activation contributes to a hyperinflammatory state, which has been linked to tissue damage and systemic inflammation (35).
In a chronic inflammatory setting, sustained inflammasome activation, together with RAGE (Receptor for Advanced Glycation End-products) signalling, may promote an environment favourable for amyloid deposition. Elevated pro-inflammatory cytokines, particularly IL-1β, can influence the processing of amyloid precursor protein (APP), leading to the increased production and deposition of amyloid-beta (Aβ), which has implications for neurodegenerative conditions.(36)
RAGE activation by advanced glycation end-products (AGEs) enhances ROS production and NF-κB signalling, further potentiating inflammasome activation and cytokine release.
The NLRP3 inflammasome plays a pivotal role in the development of central sensitization, particularly through its activation in glial cells like microglia and astrocytes. Upon activation, microglia release IL-1β, a cytokine known to increase neuronal excitability by potentiating NMDA receptor function and suppressing GABAergic inhibitory pathways. This creates a hyperexcitable neuronal state, which underpins central sensitization observed in chronic pain syndromes, including fibromyalgia, long COVID, and other neuroinflammatory conditions. The persistent release of IL-1β and IL-18 exacerbates neuroinflammation, disrupting pain regulation mechanisms in the CNS and lowering pain thresholds.
In addition, mitochondrial dysfunction and excessive production of reactive oxygen species (ROS), frequently observed in central sensitization, serve as triggers for NLRP3 inflammasome activation. Dysregulated mitochondrial dynamics within neurons and glial cells sustain a cycle of inflammasome activation, cytokine release, and further oxidative stress. This creates a self-reinforcing loop of neuroinflammation and central sensitization, contributing to the persistence of symptoms in chronic fatigue, fibromyalgia, and post-viral syndromes like long COVID.
The NLRP3 inflammasome emerges as a critical link between mitochondrial dysfunction, chronic neuroinflammation, and central sensitization, offering potential therapeutic targets for conditions like long COVID and fibromyalgia.
RAGE (receptor for advanced glycation endproducts)
RAGE (receptor for advanced glycation endproducts) is a multi-ligand pattern recognition receptor expressed on immune, endothelial and epithelial cells. Its activation significantly impacts on astrocyte function by promoting inflammation, cellular activation, and altering neurotransmitter release. These changes can significantly impact brain homeostasis and play a role in both physiological and pathological processes.
Activated astrocytes show morphological changes and altered function. Excessive or prolonged RAGE signalling of astrocytes can lead to apoptosis and cell death. (49) RAGE activation can modulate astrocyte-neuron communication and triggers the release of glutamate from astrocytes which can impact synaptic signalling and potentially contribute to excitotoxicity in sensitization. (49) It stimulates production of reactive oxygen species which can lead to cellular damage and dysfunction.(37)
Excessive glutamate release driven by RAGE signalling in astrocytes can over-activate NMDA receptors in neurons, leading to excitotoxic damage and contributing to chronic pain sensitization and neurodegenerative processes.
RAGE signals activation of NF-κB and RAGE itself is upregulated by NF-κB. In conditions there is a large amount of RAGE ligands this establishes a positive feed-back cycle, which leads to chronic inflammation. This chronic condition is then believed to alter the micro- and macrovasculature, resulting in organ damage or even organ failure. (Figure 3) RAGE has been linked to several chronic diseases which are thought to result from vascular damage.(38) RAGE signalling in astrocytes can impact neurovascular function, potentially contributing to cerebral hypoperfusion (39)
In neurodegenerative diseases like Alzheimer's and Parkinson's, RAGE-mediated astrocyte activation may contribute to chronic neuroinflammation (39) RAGE activation is associated with diabetes and its complications especially nephropathy, retinopathy, cardiovascular disease,(40) and in obesity with chronic low-grade inflammation, insulin resistance and adipose tissue dysfunction.(41)
RAGE promotes atherosclerosis by enhancing vascular inflammation, increasing oxidative stress and promoting foam cell formation.(42) In hypertension it contributes to vascular dysfunction, increased oxidative stress (42) and activates the renin-angiotensin-aldosterone system.(60) In Chronic Kidney Disease it increases inflammation, fibrosis, oxidative stress and progression of kidney dysfunction. (40) It also plays a role in rheumatoid arthritis. (41)
Despite disease-specific manifestations, RAGE activation shares common mechanisms that drive chronic inflammation and tissue dysfunction. These include:
Inflammation: RAGE signalling activates NF-κB, leading to the production of pro-inflammatory cytokines. (40) (43)
Oxidative Stress: RAGE activation stimulates NADPH oxidase, increasing ROS production (42)
Fibrosis: RAGE signalling promotes the activation of TGF-β pathways, leading to excessive extracellular matrix production (40)
Cellular Dysfunction: RAGE activation can impair the function of various cell types, including endothelial cells, neurons, and podocytes (41)(43)
Vascular Complications: RAGE contributes to endothelial dysfunction, atherosclerosis, and vascular calcification
Metabolic Dysregulation: RAGE activation is associated with insulin resistance and altered glucose metabolism (42)
Protein Aggregation: In neurodegenerative diseases, RAGE can promote the accumulation of pathological protein aggregates (42)
RAGE plays a significant role in the pathophysiology of COVID-19 by perpetuating inflammation and creating a self-sustaining inflammatory loop. This loop drives persistent immune activation, tissue damage, and chronic inflammation, contributing to both acute severity and long-term sequelae, such as Long COVID.
Targeting RAGE and its downstream signalling pathways offers a promising approach to mitigating chronic inflammation and its associated sequelae, including neurodegeneration, metabolic dysfunction, and post-viral syndromes like Long COVID.
Figure 3. The TLR4/RAGE Loop Signalling
This figure demonstrates the self-sustaining TLR4/RAGE signalling loop, perpetuating chronic inflammation through IL-1β, IL-6, and TNFα overexpression.
“High serum concentrations of S100A8/A9 trigger TLR4 and RAGE to activate the TIRAP+Md88 to NFkB and AP-1 signalling cascade, which results in hyper-expression of pro-inflammatory IL-1b and IL-6, which is secreted by the activated cells. High levels of serum IL-1b trigger IL-1R and the MyD88 to NFkB signalling pathway that upregulates the expression of new TLR4 and RAGE. High levels of serum IL-6 trigger IL-6R and the JAK/STAT signalling pathway which induces the expression of more pro-inflammatory S100A8 and S100A9 genes. After translation of the mRNA to polypeptides, S100A8/A9 hetero-dimer is secreted and the high concentrations in the serum trigger more TLR4 and RAGE, completing a pro-inflammation circuit, which does not require viral protein to persist.”(44)
Source: Holms, R. Long COVID (PASC) Is Maintained by a Self-Sustaining Pro-Inflammatory TLR4/RAGE-Loop of S100A8/A9 > TLR4/RAGE Signalling, Inducing Chronic Expression of IL-1b, IL-6 and TNFa: Anti-Inflammatory Ezrin Peptides as Potential Therapy.(44)
NF-κB / CCL2 activation
TLR4 activation, potentially triggered by SARS-CoV-2 spike protein or other damage-associated molecular patterns (DAMPs), initiates a signalling cascade that leads to NF-κB activation (45) through both MyD88-dependent and TRIF-dependent pathways.(46) (Figure 1) The MyD88-dependent pathway predominates in acute responses, while the TRIF-dependent pathway contributes to prolonged inflammation, further sustaining NF-κB and CCL2 signalling in chronic conditions.
In Long COVID, residual viral components like the SARS-CoV-2 spike protein continuously stimulate TLR4, leading to persistent NF-κB activation and CCL2 upregulation. This chronic stimulation maintains neuroinflammation and glial activation, contributing to ongoing symptoms.
TLR4 / NF-κB / CCL2 activation plays a central role in the development and persistence of central sensitization by mediating neuroinflammation, glial cell activation, and neurotransmitter dysregulation. Its involvement in both peripheral and central mechanisms highlights it as a promising target for therapeutic interventions aimed at reducing chronic pain and hypersensitivity in conditions such as POTS, Long COVID, fibromyalgia, and other chronic pain syndromes.
Immune System Activation and Dysregulation in COVID
The initial inflammatory response triggers a self-sustaining pro-inflammatory feedback loop, known as the TLR4/RAGE-loop which maintains chronic expression of IL-1β, IL-6, and TNF-α. TLR4 activation, potentially triggered by SARS-CoV-2 spike protein or other damage-associated molecular patterns (DAMPs), initiates a signalling cascade that leads to NF-κB activation through both MyD88-dependent and TRIF-dependent pathways (45)(46).
Triggering TLR4 Activation:
TLR4 is activated by pathogen-associated molecular patterns (PAMPs) like viral RNA, or damage-associated molecular patterns (DAMPs) like high mobility group box-1 (HMGB1) and oxidised phospholipids.
In Long COVID, viral remnants (e.g., SARS-CoV-2 spike proteins) persistently stimulate TLR4, perpetuating inflammatory signalling
In POTS, secondary triggers such as ischaemia-reperfusion from poor blood flow regulation or oxidative stress may also activate TLR4.
NF-κB activation results in the transcription and production of various proinflammatory cytokines, including:
Interleukin-1β (IL-1β)
Interleukin-6 (IL-6)
Tumour Necrosis Factor-α (TNF-α)
Interleukin-12 (IL-12) (5)
The inflammatory cascade also leads to the production of chemokines, with CCL2 (also known as MCP-1) playing a significant role.
CCL2 Upregulation: TLR4/NF-κB activation induces the expression of CCL2.(6) NF-κB activation activates the CCL2/CCR axis which plays a key role in the immunopathogenesis of COVID-19.(45) CCL2 is increasingly recognized as a key mediator in the development and maintenance of central sensitization.
Monocyte Recruitment: Elevated CCL2 levels promote the recruitment and infiltration of monocytes into affected tissues (45)
Perpetuation of Inflammation: The recruited monocytes further contribute to the inflammatory environment, creating a self-sustaining cycle (47)
CCL2 plays a central role in the development and persistence of central sensitization by mediating neuroinflammation, glial cell activation, and neurotransmitter dysregulation. Its involvement in both peripheral and central mechanisms highlights it as a promising target for therapeutic interventions aimed at reducing chronic pain and hypersensitivity in conditions such as POTS, Long COVID, fibromyalgia, and other chronic pain syndromes.
CCL2 in Central Sensitization
CCL2 Production:
NF-κB upregulates CCL2 expression. Elevated levels of CCL2 are found in conditions of chronic inflammation, including Long COVID and POTS.
CCL2 attracts monocytes, macrophages, and microglia to sites of inflammation, perpetuating immune activation.
Neuroinflammation:
In the central nervous system (CNS), CCL2 contributes to the recruitment and activation of microglia, the resident immune cells in the CNS.
Activated microglia release neurotoxic mediators like prostaglandins, reactive oxygen species (ROS), and IL-1β, sensitizing neurons and reducing the threshold for pain or autonomic dysregulation.
Impact on Sensory Neurons:
CCL2 binds to CCR2 receptors on sensory neurons in the dorsal root ganglia (DRG), enhancing the excitability of nociceptive and autonomic circuits.
This mechanism is critical in amplifying central sensitization, contributing to dysautonomia, widespread pain, and fatigue commonly seen in POTS and Long COVID.
Downstream Effects of TLR4/NF-κB/CCL2 Axis in Sensitization
Sustained Peripheral and Central Inflammation:
Peripheral immune cell recruitment (monocytes and T cells) and activation by CCL2 exacerbates systemic inflammation.
The persistence of these signals may explain the chronicity of symptoms in Long COVID and the overlap with POTS.
Breakdown of the Blood-Brain Barrier (BBB):
TLR4 activation and subsequent production of cytokines like TNF-α and IL-6 can compromise BBB integrity, allowing peripheral inflammatory mediators and immune cells to enter the CNS.
Elevated CCL2 levels can promote further BBB disruption by enhancing endothelial permeability.
Neuroimmune Feedback Loops:
CCL2, TNF-α, and IL-1β create a feedback loop within the CNS, leading to chronic activation of microglia and astrocytes.
This loop reinforces central sensitization, sustaining autonomic and pain dysfunctions.
Dysregulation of Autonomic Circuits:
In POTS, the pro-inflammatory cytokine milieu disrupts the balance of the autonomic nervous system (sympathetic overactivity and parasympathetic underactivity).
This dysregulation exacerbates tachycardia, fatigue, and other autonomic symptoms.
Enhanced Pain and Hyperalgesia:
Central sensitization results in hyperresponsiveness to nociceptive inputs, partly mediated by CCL2-driven microglial activation and dorsal horn sensitization.
6. Neurotransmitter Imbalance
Inflammation-induced changes in neurotransmitter systems contribute to central sensitization with Serotonin depletion where Chronic inflammation may lead to reduced serotonin levels (48)
Glutamate Dysregulation: Neuroinflammation can alter glutamatergic signalling, enhancing pain sensitivity (49) This has been confirmed in clinic amino acid studies.
7. Autonomic Dysfunction. In POTS and Long COVID, central sensitization affects autonomic nervous system function:
Sympathetic Overactivation: Persistent inflammation can lead to increased sympathetic nervous system activity (48)
Baroreceptor Reflex Impairment: Inflammatory processes may interfere with normal baroreceptor function, contributing to orthostatic intolerance (48)
Implications for POTS and Long COVID
The central sensitization resulting from this inflammatory cascade contributes to various symptoms observed in POTS and Long COVID:
Cognitive Dysfunction: Neuroinflammation and neurotransmitter imbalances can lead to "brain fog" and other cognitive issues (48)
Fatigue: Persistent inflammation and autonomic dysfunction contribute to chronic fatigue (47)
Pain Hypersensitivity: Central sensitization enhances pain perception, leading to widespread pain and hyperalgesia (49)
Orthostatic Intolerance: Autonomic dysfunction resulting from central sensitization contributes to the characteristic symptoms of POTS (48)
Conclusion
Central sensitization in conditions such as POTS, Long COVID, and fibromyalgia is sustained by persistent TLR4/RAGE activation and downstream inflammatory signalling cascades. The interplay between pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), CCL2-driven neuroimmune responses, and glial activation underlies chronic neuroinflammation, pain hypersensitivity, autonomic dysfunction, and neurotransmitter imbalances.
These processes compromise blood-brain barrier (BBB) integrity, amplify autonomic dysregulation, and contribute to systemic inflammation. Importantly, the persistence of these signals reinforces a self-sustaining inflammatory loop, perpetuating symptoms such as widespread pain, fatigue, cognitive dysfunction (brain fog), and orthostatic intolerance.
Understanding the TLR4/NF-κB/CCL2 axis and its role in central sensitization highlights promising therapeutic opportunities. Targeted interventions such as TLR4 antagonists, NF-κB inhibitors, CCR2 blockers, and mast cell stabilizers, hold potential to disrupt the inflammatory feedback loops, restore neuroimmune balance, and alleviate chronic symptoms.
Future research focusing on precision therapies that modulate these inflammatory pathways may pave the way for novel treatments, offering hope for patients with persistent symptoms associated with POTS, Long COVID, and fibromyalgia. By addressing both peripheral and central mechanisms, these strategies aim to reduce symptom chronicity and improve patient outcomes.
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