Dysautonomia as a Neuroimmune–Metabolic Disorder: A Unified Model Linking TLR4 Activation, Brainstem Hypoxia, and Autonomic Plexus Dysfunction

Dr Graham Exelby May 2025

Contents:

1.     Abstract

2.     Introduction

3.     Section 1- Linking Immune dysregulation to Metabolic, Microglial, Astrocyte and Mast Cell Dysregulation and DNA Mutations identified in POTS and Long COVID

a.     TLR4 Priming and Immune Sensitisation

b.     Hypoxia and Its Impact on Mitochondrial and Metabolic Signalling in Dysautonomia

c.     The Primary Players

d.     Section Summary: TLR4–RAGE–CCL2 Axis in Neuroimmune Sensitization

e.     Medication for Consideration in Management

4.     Section 2. Anatomical and Functional Integration of Brainstem with the Cardiac and Coeliac Plexuses

5.     Conclusion

Abstract

This paper proposes a unifying mechanistic framework for dysautonomia, including Postural Orthostatic Tachycardia Syndrome (POTS) and Long COVID, based on TLR4-mediated microglial priming, neuroimmune sensitisation, and mitochondrial dysfunction. We argue that brainstem hypoperfusion—driven by immune activation, metabolic derangement, and structural venous/lymphatic impairment—sits at the nexus of autonomic instability.

The convergence of TLR4–RAGE–CCL2 signalling with mitochondrial metabolic collapse, particularly involving PDH inhibition and malate-aspartate shuttle failure, sustains a chronic excitatory glial-mast cell loop that underpins the relapsing, multisystemic phenotype of dysautonomia.

This model integrates anatomical dysregulation at the cardiac and coeliac plexuses, mechanical triggers (e.g., vertebral rotation, venous obstruction), and molecular drivers (e.g., genetic polymorphisms, persistent DAMP/PAMP signalling) into a coherent neuroimmune-metabolic cascade. We propose the gastro-cranial hydraulic continuum as a central anatomical substrate for preload failure and central sensitisation, offering a novel diagnostic and therapeutic lens for these under-recognized syndromes.

Introduction

Dysautonomia encompasses a heterogeneous group of syndromes characterized by disrupted autonomic nervous system (ANS) regulation. While traditionally considered idiopathic or functional in origin, recent evidence highlights immune, metabolic, and structural underpinnings that converge on central autonomic control centres, particularly the brainstem.

Toll-like receptor 4 (TLR4) and its co-receptors are emerging as central regulators of this process, mediating neuroimmune priming in response to pathogen- and damage-associated molecular patterns (PAMPs and DAMPs). In susceptible individuals—via genetic polymorphisms or environmental exposures—this initiates a feed-forward cascade of glial activation, mitochondrial dysfunction, and impaired autonomic signalling.

Beyond immune priming, brainstem hypoperfusion and regional hypoxia—often resulting from mechanical obstruction of venous and lymphatic outflow—compromise mitochondrial energetics and exacerbate TLR4-mediated inflammation. These pathophysiological mechanisms extend peripherally to the cardiac and coeliac plexuses, amplifying autonomic instability and systemic symptoms. This paper presents an integrated model linking TLR4-driven neuroimmune sensitization, mitochondrial failure (particularly PDH inhibition), structural compression, and anatomical dysregulation of key autonomic relay centres in the genesis of dysautonomia syndromes such as POTS and Long COVID.

Section 1- Linking Immune dysregulation to Metabolic, Microglial, Astrocyte and Mast Cell Dysregulation and DNA Mutations identified in POTS and Long COVID

TLR4 Priming and Immune Sensitisation

Toll-like receptor 4 (TLR4) operates as a critical gatekeeper of innate immune surveillance, responsive to both exogenous pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and endogenous damage-associated molecular patterns (DAMPs) including HMGB1, S100A8/A9, and fibrinogen breakdown products.

Importantly, TLR4 signalling is not binary but exists along a spectrum of responsiveness. Repeated low-grade or sub-threshold exposures “prime” the receptor system—particularly in microglia, monocytes, mast cells, and endothelial cells—effectively lowering the activation threshold and rendering the system hypersensitive to subsequent stimuli.

This TLR4 priming converts physiological inputs (e.g., dietary emulsifiers, thermal changes, mycotoxins, barometric shifts) into triggers of pathological inflammatory responses. In dysautonomia-associated syndromes—such as POTS, ME/CFS, mast cell disorders, and Long COVID—this results in chronic sensitisation. Patients report exaggerated responses to exertion, orthostasis, temperature changes, and metabolic stressors, reflecting a deeper immune-metabolic conditioning rather than mere heightened perception.

At the molecular level, recent work by Lauterbach et al. 2021 (1) provides a mechanistic underpinning for this phenomenon. TLR4 activation in macrophages does not merely trigger inflammatory transcription—it also initiates rapid metabolic reprogramming, including enhanced glycolytic flux and TCA cycle throughput, facilitating increased production of acetyl-CoA. This, in turn, augments histone acetylation, a crucial epigenetic modification where acetylation of histones alters accessibility of chromatin and allows DNA binding proteins to interact with exposed sites to activate gene transcription and downstream cellular functions.  

This reshapes the epigenetic landscape in a manner that favours persistent, high-fidelity transcription of pro-inflammatory gene sets. MyD88 and TRIF adaptor proteins initiate this process via ATP-citrate lyase (ACLY) activation, thus tying immune memory and metabolic status into a unified transcriptional output. This may help explain why patients with prior infection, trauma, or toxin exposure exhibit long-lasting immune dysregulation.

Figure 1. Toll-like Receptor Signalling Rewires Macrophage Metabolism and Promoting Histone Acetylation via ATP-Citrate Lyase

Source:  Lauterbach et al (2019). Toll-like Receptor Signaling Rewires Macrophage Metabolism and Promotes Histone Acetylation via ATP-Citrate Lyase (1)

Genetic polymorphisms in TLR4 (e.g., rs4986790/rs4986791), and downstream effectors such as RAGE (AGER), CCL2 (MCP-1), and NF-κB subunits, appear enriched in Long COVID and POTS cohorts, according to several recent exome-sequencing studies, including Vittone and Exelby 2023 (2). These variants create a constitutional predisposition toward hyperinflammatory states, particularly when compounded by environmental stressors like viral persistence, gut barrier breakdown, or mould exposure (e.g., trichothecenes, gliotoxin).

Environmental exposures act not as isolated causes but as amplifiers of a pre-primed system. Notably, persistent microbial translocation from a compromised gut barrier, biofilm-released LPS, and mould-derived mycotoxins, perpetuate TLR4–RAGE–NF-κB signalling loops. These engage central glial activation, perivascular inflammation, and mast cell–microglia–astrocyte crosstalk, culminating in autonomic destabilisation and widespread symptom amplification.

Thus, sensitisation in this framework is not merely a perceptual or nociceptive amplification but a deeply rooted immunometabolic and glioneurovascular dysfunction. It aligns with the broader construct of immune memory and metabolic reprogramming, where prior insult (infection, stress, toxicant exposure, or injury) conditions future responsiveness via TLR4-dependent pathways. The result is a self-sustaining, neuroimmune-sensitised state that underpins much of the clinical variability seen in dysautonomia syndromes.

In clinical terms, this translates into autonomic dysfunction, pain amplification, and fatigue, driven by neuroimmune sensitisation rather than structural lesions or psychosomatic constructs.  Thus, TLR4 priming is best understood as a molecular conditioning event—a convergence point where immune memory, metabolic rewiring, and environmental amplification produce the persistent and relapsing phenotype typical of chronic dysautonomia syndromes.

Hypoxia and Its Impact on Mitochondrial and Metabolic Signalling in Dysautonomia

Hypoxia, both regional and systemic, emerges as a critical amplifier of immune and metabolic dysfunction in dysautonomia syndromes. Whether resulting from venous congestion (e.g. Nutcracker syndrome, thoracic outlet obstruction), sympathetic-driven vasospasm, intracranial hypertension, capillary rarefaction, or impaired neurovascular coupling, oxygen deprivation drives a cascade of biochemical adaptations that disrupt core mitochondrial pathways and immune homeostasis.

One of the earliest molecular targets of hypoxia is the pyruvate dehydrogenase (PDH) complex, the enzyme responsible for converting pyruvate into acetyl-CoA and linking glycolysis to the TCA cycle. Hypoxia stabilizes hypoxia-inducible factor-1α (HIF-1α), which in turn upregulates pyruvate dehydrogenase kinases (PDKs).

PDKs phosphorylate and inhibit PDH, thereby diverting pyruvate away from mitochondrial oxidation and toward cytosolic lactate production, even in the absence of anaerobiosis. This creates a “pseudo-hypoxic” metabolic state and contributes to the elevated lactate observed in post-exertional malaise (PEM) and tilt-provoked testing in POTS patients, despite normoxia at the systemic level.

Concomitantly, hypoxia impairs the malate–aspartate shuttle, a vital mechanism for shuttling NADH-reducing equivalents from the cytosol into the mitochondria. This shuttle is dependent on a finely tuned interplay of aspartate and malate gradients across the mitochondrial membrane, and dysfunction leads to cytosolic NADH accumulation, impaired oxidative phosphorylation, and redox stress. Fluge et al. 2016 (3) demonstrated that aspartate availability is reduced in ME/CFS patients, a finding which aligns with our clinic’s urinary metabolomics data showing low aspartate and elevated glutamate, suggesting impaired transamination and stalled NADH clearance.

Figure 2:  Proposed mechanism of ME/CFS linked to amino acid catabolism.

Category I: amino acids are converted to pyruvate, and therefore depend on PDH to be further oxidized. These are alanine (Ala), cysteine (Cys), glycine (Gly), serine (Ser), and threonine (Thr).

Category II: amino acids that enter the oxidation pathway as acetyl-CoA, which directly and independently of PDH fuels the TCA cycle for degradation to CO2. These are isoleucine (Ile), leucine

(Leu), lysine (Lys), phenylalanine (Phe), tryptophan (Trp), and tyrosine (Tyr).

Category III consists of amino acids that are converted to TCA cycle intermediates, thereby replenishing and supporting the metabolic capacity of the cycle- histidine (His), and proline (Pro)

The asterisks indicate the amino acids significantly reduced in ME/CFS patients.

Source: Fluge et al.,2016. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. (3)

The metabolic consequences of these disruptions are multifold:

• Reduced ATP production, contributing to exertional intolerance and neuromuscular fatigue.

• Accumulation of lactate and proton load, exacerbating local acidosis and pain.

• Failure to generate mitochondrial acetyl-CoA, impairing both TCA cycle flux and histone acetylation, the latter of which is crucial for resolving inflammatory gene programs.

• Diminished GABA synthesis, as the glutamate–aspartate–GABA axis is disrupted, leading to excitotoxicity, autonomic lability, and central sensitisation.

Moreover, hypoxia itself activates RAGE signalling via upregulation of its ligands (e.g. HMGB1, Se Amyloid A, S100 proteins) and fuels NF-κB–driven inflammation, closing the feed-forward loop between immune dysregulation and metabolic paralysis. This model supports a unifying view where vascular, mitochondrial, and immunological dysfunction converge, not merely coexisting but interacting through shared molecular levers.

The Primary Players

Toll-like receptor (TLR) activation

Toll-like receptor 4 (TLR4) operates as a critical gatekeeper of innate immune surveillance, responsive to both exogenous pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and endogenous damage-associated molecular patterns (DAMPs) including HMGB1, S100A8/A9, and fibrinogen breakdown products.

Figure 2. TLR4 Signalling Pathway.  

This schematic provides a comprehensive overview of the TLR4 signalling cascade, including both MyD88-dependent and TRIF-dependent pathways, culminating in the production of pro-inflammatory cytokines.

Source: Mantovani S, Oliviero B, Varchetta S, Renieri A, Mondelli MU.(2023)TLRs: Innate Immune Sentries against SARS-CoV-2 Infection. Int J Mol Sci.(4)

Toll-like receptor (TLR) activation induces inflammatory responses in macrophages by activating temporally defined transcriptional cascades. Shortly after TLR4 activation, macrophages increased glycolysis and tricarboxylic acid (TCA) cycle volume. Metabolic tracing studies revealed that TLR signalling redirected metabolic fluxes to generate acetyl-Coenzyme A (CoA) from glucose resulting in augmented histone acetylation. Signalling through the adaptor proteins MyD88 and TRIF resulted in activation of ATP-citrate lyase, which in turn facilitated the induction of distinct LPS-inducible gene sets.

1.     Microglia: The Brain's Innate Immune Sentinels

Microglia are the resident macrophages of the central nervous system and serve as the brain’s primary innate immune sensors. Under physiological conditions, they maintain synaptic homeostasis, prune neural circuits, and monitor the extracellular environment. However, in the setting of TLR4 or RAGE activation, microglia rapidly transition into a pro-inflammatory phenotype, releasing cytokines (e.g. TNF-α, IL-1β), chemokines (notably CCL2), and reactive oxygen species.

NF-κB is the central transcriptional driver of this activation. Critically, this microglial reactivity can be prolonged and region-specific—particularly affecting the nucleus tractus solitarius (NTS), locus coeruleus, and hypothalamus, which are integral to autonomic control.  Sustained microglial activation contributes to baroreceptor dysfunction, sympathetic overactivity, and central sensitization seen in POTS and ME/CFS. In some patients, chronic microglial priming creates a state of "neuroimmune memory", amplifying responses to otherwise innocuous stimuli and promoting autonomic instability.

2.     Astrocytes: Metabolic Modulators and Inflammatory Amplifiers

Astrocytes are glial cells with extensive metabolic and structural roles, forming part of the blood–brain barrier and modulating neuronal excitability, ion balance, and neurotransmitter clearance. In neuroinflammatory conditions, they act as key amplifiers of immune signalling. Activated by IL-1β, HMGB1, and CCL2, astrocytes upregulate RAGE and TLR4, becoming active participants in the NF-κB signalling cascade.

Their activation results in production of IL-6, glutamate, and S100B, all of which worsen neuronal excitotoxicity and glial crosstalk.

• Glutamate release occurs via vesicular mechanisms involving Synaptotagmins 4/7/11 and Gq-coupled receptors (e.g., P2Y1R), influencing synaptic plasticity through extrasynaptic NMDA receptors. (de Ceglia et al. 2023 (5)) (Cuellar-Santoyo et al.2023 (6))

• IL-6 secretion is upregulated by inflammatory signals (IL-1β, TNF-α)    (Codeluppi et al. 2014 (7)) or TLR4 activation. (Krasovska & Doering.  2018 (8))

• S100B production modulates astrocyte morphology/migration via Src-PI3K pathways, and amplifies nitric oxide release in glia, with autoregulatory feedback controlling its expression. (Brozzi et al.  2009 (9) (Hernández-Ortega et al. 2024. (10)) (Petrova et al 2000(11))

  
  

Importantly, astrocytes respond to hypoxia and mitochondrial dysfunction, further linking them to the metabolic phenotype seen in Long COVID and chronic dysautonomia. In POTS, dysregulated astrocytes may impair neurovascular coupling and blood–brain barrier integrity, contributing to symptoms such as brain fog, orthostatic headaches, and central fatigue.

3.     Mast Cells: Peripheral Sensors with Central Impact

Mast cells are best known for their role in allergic responses, but they also play a central role in sterile inflammation and neuroimmune crosstalk. Located strategically around blood vessels, nerve endings, and autonomic ganglia, mast cells are activated not only by IgE, but also by DAMPs, cytokines, CRH, and neuropeptides.

Once activated, they degranulate, releasing histamine, tryptase, prostaglandins, leukotrienes, and importantly, TNF-α and IL-6, which directly stimulate microglial and astrocytic activation. Mast cells also express TLR4 and RAGE, allowing them to be directly activated by LPS, HMGB1, and oxidative stress.

This places them as first responders in the periphery and CNS, contributing to vascular permeability, postural tachycardia, brainstem neuroinflammation, and central pain amplification. In many patients with POTS and ME/CFS, mast cell overactivity (even without classic MCAS) manifests as flushing, hives, GI dysmotility, and labile blood pressure—linking immune dysregulation with autonomic instability.

4.     NF-κB: The Master Switch of Inflammation

Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a pivotal transcription factor acting as the master regulator of the innate immune response. It is rapidly activated in response to diverse cellular stressors—including pathogen-associated molecular patterns (PAMPs) via Toll-like receptors, damage-associated molecular patterns (DAMPs) via RAGE, as well as cytokines like TNF-α and IL-1β, hypoxia, and oxidative stress.

Once activated, NF-κB translocates to the nucleus where it induces transcription of hundreds of pro-inflammatory genes including CCL2, IL-6, TNF-α, COX-2, and iNOS, (all if which have been noted in DNA studies in POTS and Long-COVID by Vittone and Exelby.2023 (2) to have DNA mutations present.)  This effectively sustains a chronic inflammatory loop.

In dysautonomia and related post-viral syndromes, NF-κB activation drives neuroinflammation, endothelial dysfunction, mitochondrial stress, and autonomic dysregulation. Notably, it primes glial cells, sensitizes baroreflex circuits, and promotes perivascular immune cell recruitment.

Chronic or inappropriate NF-κB signalling contributes to a feed-forward loop in which sterile inflammation becomes self-sustaining—independent of ongoing infection—and underlies the persistent symptoms seen in POTS and Long COVID.

Therapeutic approaches targeting NF-κB directly are under investigation, but upstream modulation via TLR4/RAGE blockade, N-acetylcysteine, low-dose naltrexone, or nicotinamide derivatives offers more practical clinical potential.

5.     RAGE: A Perpetuator of Sterile Inflammation and Neuroimmune Crosstalk

The Receptor for Advanced Glycation End Products (RAGE) is an underrecognized but critically important pattern recognition receptor (PRR) involved in sustaining sterile inflammation—that is, inflammation not caused by pathogens but by endogenous stress signals.

RAGE binds a range of ligands including HMGB1, S100 proteins, amyloid fibrils, oxidized lipids, and advanced glycation end products (AGEs)—many of which are elevated in tissue hypoxia, oxidative stress, or metabolic dysfunction. Once activated, RAGE initiates intracellular signalling cascades that culminate in NF-κB activation, amplifying production of CCL2, IL-6, and other inflammatory mediators.

In dysautonomia, RAGE is particularly relevant to vascular inflammation, endothelial barrier dysfunction, microglial activation, and central sensitization. Its expression is heightened in the brainstem and peripheral nerves under conditions of chronic hypoxia or mitochondrial impairment—both key features in POTS and post-COVID syndromes.

RAGE also localizes to cerebral endothelial cells, vagal afferents, and the coeliac and cardiac plexuses, placing it anatomically and mechanistically at the centre of autonomic disruption.

Importantly, RAGE activation is not self-limiting; it amplifies its own ligands through oxidative feedback, establishing a pathological positive feedback loop. This makes it a critical target in conditions driven by unresolved immune activation, with famotidine, nicotinamide, and TLR4-RAGE inhibitors offering potential avenues for intervention.

6.     CCL2 (MCP-1) and Its Role in Dysautonomia

Chemokines are small signalling molecules, part of the broader cytokine family, that play a crucial role in directing the movement of cells, particularly leukocytes, to areas of inflammation or other biological needs. They act by binding to specific receptors on the surface of cells, triggering signals that lead to cell migration and chemotaxis (movement in response to a chemical stimulus).  

CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), is a key chemokine that orchestrates immune cell trafficking, particularly the recruitment of monocytes, memory T cells, and dendritic cells to sites of tissue inflammation.  

Although largely unfamiliar to most clinicians, CCL2 plays a pivotal role in neuroimmune dysregulation, particularly in conditions such as POTS, Long COVID, and ME/CFS where chronic low-grade inflammation persists without overt infection.

CCL2 expression is tightly regulated but becomes markedly upregulated in response to a broad range of innate immune stimuli—most notably through TLR4, RAGE (receptor for advanced glycation end products), IL-1β, TNF-α, and oxidative stress-induced NF-κB activation.

Once engaged, CCL2 establishes a feed-forward loop of inflammation and tissue infiltration, particularly in the central nervous system and autonomic ganglia, where it has been shown to activate microglia, enhance sympathetic tone, and sustain mast cell–T cell–glial crosstalk.

In dysautonomia, especially POTS, elevated CCL2 levels may reflect a persistent "sterile inflammation" phenotype, linking metabolic dysfunction, endothelial injury, and neuroimmune activation. Its overexpression also correlates with impaired baroreceptor sensitivity and brainstem gliosis in experimental models.

Importantly, CCL2 signalling is attenuated by agents such as famotidine (via modulation of histamine and IL-6), N-acetylcysteine, and upstream blockade of TLR4/RAGE pathways, offering emerging therapeutic relevance.

Genetic variations in the CCL2 gene are associated with an increased risk of developing a wide number of  diseases by activating signalling pathways, including JAK/STAT and NF-κB which can influence cell behaviour, survival, and gene expression across different cell types and tissues.

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 Mast cell activation syndrome (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.

Dysregulation of CCL2 expression has been implicated in the pathogenesis of various health conditions, including Rheumatoid Arthritis (12), IBS (13), fibromyalgia (14), chronic fatigue (15), chronic pain syndromes (12), POTS, connective tissue disease (16), ADHD (17), autism (18)(19). 

POTS Connection:

CCL2 has been found to be elevated in the serum of patients with POTS, as well as in autonomic dysfunction, 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 (21) and is thought may contribute to the disruption of the blood-brain barrier (22)

• 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. (23)

• 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 is critical in local inflammation in compressed areas.

• There is an emerging link involving CCL2 dysregulation and hypoxia-driven lysine dysregulation seen when clinic amino acid results are integrated into these pathways.   Modelling suggests that low lysine is not simply a secondary metabolic marker, but a contributing factor to connective tissue pathology when coupled with chronic CCL2-driven immune activation.  Lysine levels are frequently improved with addition of liposomal nicotinamide riboside.

• Elevated CCL2 can disrupt the function of the paraventricular nucleus (NTS) and hypothalamic paraventricular nucleus (PVN,) critical brainstem regions involved in autonomic regulation.  The PVN projects to the brainstem, particularly to areas involved in autonomic regulation like the rostral ventrolateral medulla (RVLM) and nucleus tractus solitarius (NTS). This projection allows the PVN to influence cardiovascular and respiratory function, and it is also involved in the brain's response to immune challenges. 

• CCL2 and its receptor CCR2 are expressed in central autonomic control centres like the PVN and rostral ventrolateral medulla.(22)   This can result in altered sympathetic outflow to cardiovascular organs, changes in blood pressure regulation and disruption of respiratory control.(24)(25)

• Migraine with aura: CCL2 has been implicated in the inflammation and pain associated with migraine including with aura (which has an association with dysfunction of the Locus Coeruleus and Glymphatic closure,) and implies an association with brainstem hypoxia.

Fibromyalgia Connection

Fibromyalgia (FM) is characterized by widespread musculoskeletal pain, fatigue, and cognitive disturbances. Emerging evidence suggests that CCL2 contributes to FM pathogenesis.  (García-Domínguez 2025.(26))(Zhao et al. 2019 (14))

• Elevated levels: Patients with FM exhibit increased plasma concentrations of CCL2, correlating with symptom severity. 

• Mast cell interaction: CCL2 acts as a chemoattractant for mast cells, which are found in increased numbers in FM patients. Activated mast cells release substances that sensitize nociceptors and contribute to pain. 

• Neuroinflammation: CCL2-mediated activation of glial cells in the central nervous system leads to a pro-inflammatory environment, promoting central sensitization and chronic pain.

·       Duloxetine, arguably the most effective therapy to control fibromyalgia pain may work in FMS and overlapping dysautonomia not just via serotonin–norepinephrine reuptake inhibition, but also through downregulation of CCL2, which is central to central sensitisation, mast cell–glial crosstalk, and immune-driven fatigue and pain.

CCL2 and 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.  CCL2 is upregulated in response to peripheral inflammation and nerve injury. It binds to its receptor CCR2 on various cells, including neurons and glial cells, leading to:

• Recruitment of immune cells: CCL2 attracts monocytes/macrophages to sites of injury, contributing to sustained inflammation. 

• Neuronal sensitization: CCL2 enhances excitatory synaptic transmission in the spinal cord by increasing NMDA receptor activity, particularly through the ERK-GluN2B signalling pathway. 

• Glial activation: CCL2 stimulates astrocytes and microglia, leading to the release of pro-inflammatory cytokines and further amplification of pain signals

Other areas where CCL2 dysregulation is implicated:

·       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.(27)

·       Connective tissue disease: CCL2 has been implicated in the pathogenesis of connective tissue diseases, including systemic sclerosis and rheumatoid arthritis.  

·       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.(28) It seems likely this reflects CCL2 activation from hypoxia.

• 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.

• 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.

To visually represent the intricate interplay between TLR4 signalling, RAGE activation, CCL2 expression, and the subsequent neuroimmune sensitisation involving glial and mast cell interactions, the following schematic diagrams encapsulate these pathways:

Figure 3. TLR4 and RAGE Signalling Integration: This diagram illustrates the convergence of TLR4 and RAGE pathways upon stimulation by ligands such as LPS and HMGB1, leading to downstream activation of NF-κB and MAPK pathways.

Source: Constructed by Chat GPT

Figure 4. Glial-Mast Cell Interactions in Neuroinflammation: This figure depicts the bidirectional communication between mast cells, microglia, and astrocytes, highlighting the mediators involved in neuroinflammatory processes.

Source: Carthy, Elliott & Ellender, Tommas. (2021). Histamine, Neuroinflammation and Neurodevelopment: A Review. Frontiers in Neuroscience (29)

Figure 5. TLR4 Signalling Pathway Overview: This schematic provides a comprehensive overview of the TLR4 signalling cascade, including both MyD88-dependent and TRIF-dependent pathways, culminating in the production of pro-inflammatory cytokines.

Source: Mantovani S, Oliviero B, Varchetta S, Renieri A, Mondelli MU.(2023)TLRs: Innate Immune Sentries against SARS-CoV-2 Infection. Int J Mol Sci.(4)

Figure 6. CCL2/CCR2 Axis in Inflammation: This diagram focuses on the role of the CCL2/CCR2 axis in mediating inflammatory responses, particularly in the context of TLR4 activation and its implications in neuroinflammation.

Source: Zhang et al.(2022) Role of the CCL2-CCR2 axis in cardiovascular disease: Pathogenesis and clinical implications. (30)

These visual representations can serve as valuable tools to elucidate the complex mechanisms underpinning TLR4-mediated neuroimmune sensitisation and its relevance to conditions such as POTS and Long COVID.

Section Summary: TLR4–RAGE–CCL2 Axis in Neuroimmune Sensitization

From Priming to Perpetuation: Microglial Activation and Glial–Mast Cell Looping

Once TLR4 priming is established, the central nervous system becomes increasingly susceptible to persistent neuroinflammation. Microglia, the brain’s resident immune sentinels, undergo a shift from a surveillance (M0) to a reactive phenotype (M1/M2b), driven by repeated TLR4–RAGE stimulation and metabolic stress. In this state, microglia exhibit heightened expression of NF-κB, NLRP3 inflammasome components, and pro-inflammatory cytokines including IL-1β, TNF-α, and CCL2—all of which reinforce further TLR4 engagement. Critically, microglial activation does not occur in isolation.

Astrocytes—particularly A1-reactive phenotypes—respond to these inflammatory cues by releasing excess glutamate, downregulating glutamate transporters (e.g., GLT-1/EAAT2), and reducing GABAergic tone. This creates a state of excitotoxic amplification, especially vulnerable in the brainstem, hypothalamus, and limbic networks governing autonomic and endocrine regulation.

Mast cells, strategically located along perivascular and dural surfaces as well as within the median eminence and hypothalamus, respond in parallel. Via CRH, IL-33, and substance P, they contribute to microglial recruitment and amplify central sensitisation.

The loop becomes self-sustaining: mast cell mediators (histamine, tryptase, leukotrienes) activate microglia, while microglial-derived CCL2, IL-1β, and ROS further stimulate mast cell degranulation. This glial–mast cell feedback circuit is reinforced under conditions of metabolic insufficiency, hypoxia, or impaired GABA/aspartate cycling—all common in POTS, ME/CFS, and Long COVID.

Ultimately, this establishes a maladaptive central sensitisation complex, no longer dependent on peripheral triggers. Instead, immune memory, metabolic dysfunction, and neuroglial cross-talk drive a persistent hypersensitive state, destabilising baroreflexes, autonomic tone, and systemic homeostasis.

Key Components:

1. TLR4 Activation:

   • Engaged by PAMPs (e.g., LPS) and DAMPs (e.g., HMGB1, S100A8/A9).

   • Utilizes co-receptors MD-2 and CD14 for ligand recognition.

   • Initiates MyD88-dependent and TRIF-dependent signalling pathways.

2. RAGE Engagement:

   • Activated by advanced glycation end-products (AGEs) and DAMPs like HMGB1.

   • Amplifies inflammatory signalling cascades synergistically with TLR4.

3. Downstream Signalling:

   • Activation of NF-κB and MAPK pathways leading to transcription of pro-inflammatory cytokines.

   • Induction of CCL2 (MCP-1) expression, promoting monocyte recruitment.

4. Neuroimmune Sensitization:

   • CCL2-mediated recruitment of immune cells to the CNS.

   • Microglial and astrocyte activation perpetuating neuroinflammation.

   • Mast cell degranulation contributing to blood-brain barrier permeability and further immune cell infiltration.

Medication for Consideration in Management

1. Low dose naltrexone (LDN) modulates the TLR4/ NF-κB pathway primarily by antagonizing TLR4, thereby suppressing pro-inflammatory signalling. Low Dose Naltrexone (LDN) modulates the TLR4/ NF-κB pathway primarily by antagonizing TLR4, thereby suppressing pro-inflammatory signalling.  It binds to TLR4’s co-receptor MD2, inhibiting downstream NF-κB activation and reducing cytokines like TNF-α, IL-6, and IL-1β.  It binds to TLR4’s co-receptor MD2, inhibiting downstream NF-κB activation and reducing cytokines like TNF-α, IL-6, and IL-1β.   While LDN does not directly block NF-κB or MAPK pathways, it attenuates NF-κB activity indirectly via SIRT1 upregulation, enhancing anti-inflammatory effects.   This dual action curbs chronic inflammation and restores immune balance in autoimmune and metabolic disorders.(Zhang et al. 2020 (31))(Cant et al 2017 (32))(Wang et al. 2016 (33))(Choubey et al. 2020 (34))

2. Famotidine histamine H2R inhibition + CCL2 modulation via IL-6 suppression- activates the vagus nerve inflammatory reflex, leading to attenuation of cytokine storm in a mouse model of severe inflammation. This effect is mediated via the α7 nicotinic acetylcholine receptor (α7nAChR) pathway, resulting in reduced levels of pro-inflammatory cytokines such as TNF and IL-6.  It’s role in Long COVID transcends its classical H2-receptor effects, acting instead on key nodes of immune dysregulation, including RAGE/NF-κB, CCL2, and the mast cell–microglial–astrocytic axis. Through modulation of these pathways, famotidine interrupts the chronic feedforward loop sustaining post-viral inflammation and neuroimmune sensitization.

3. Nicotinamide Riboside- NAD+/SIRT1 enhancement and epigenetic reprogramming

4. Cromolyn- mast cell stabilizer By targeting the mast cell initiators of the RAGE/NF-κB/CCL2 axis, cromolyn may disrupt the core microglial–mast cell–astrocyte feedforward loop driving persistent neuroinflammation

5. H1 -blockers eg fexofenadine, cetirizine and ketotifen:

   1. Fexofenadine is a peripheral anti-histamine, especially in histaminergic symptom clusters. It lacks mast cell stabilization and does not cross the BBB, limiting utility in neuroinflammatory Long COVID

   2. Cetirizine offers slightly better immune modulation, with minimal central effects, and may be useful in mixed cases with both immune and allergic phenotypes

   3. Ketotifen stands out as the only H1 blocker with central anti-neuroinflammatory effects, particularly through mast cell stabilization and inhibition of CCL2, IL-6, VEGF, and glial activation. It is the most likely of currently available medication to modulate RAGE/NF-κB feedforward loops affecting microglia–astrocyte–mast cell crosstalk in Long COVID, though sedation is a limiting factor.

6. N-acetylcysteine (NAC) NAC supports glutathione synthesis, reduces oxidative stress, inhibits NF-κB-driven inflammation, and modulates glutamate excitotoxicity—making it a valuable adjunct in dysautonomia, particularly when redox imbalance, mitochondrial dysfunction, or central sensitization is present. It may also reduce fibrin-amyloid aggregates and support endothelial repair in Long COVID and POTS. However, high doses can act as pro-oxidants, and NAC may trigger symptoms in sulphur-sensitive or mast cell–reactive individuals. It should be introduced cautiously and may require co-administration with B vitamins, ALA, or taurine to optimize efficacy and tolerability, and monitored by clinicians proficient in its use.

   
   

Section 2. Anatomical and Functional Integration of Brainstem with the Cardiac and Coeliac Plexuses

The brainstem—specifically the medulla oblongata and the rostral ventrolateral medulla (RVLM)—serves as the central command centre for autonomic regulation. Within this hub, the nucleus tractus solitarius (NTS) integrates baroreceptor and visceral afferent signals and communicates with the dorsal motor nucleus of the vagus and sympathetic premotor neurons in the RVLM. These nuclei regulate descending output to both the cardiac and coeliac plexuses via sympathetic fibres originating from the intermediolateral columns of the spinal cord (T1–T12), and parasympathetic fibres via the vagus nerve.

The cardiac plexus receives sympathetic input from T1–T4 via the cervical and stellate ganglia and parasympathetic fibres from the vagus nerve. It modulates heart rate, contractility, and coronary tone.

The coeliac plexus, in contrast, integrates sympathetic fibres from T5–T12 via the greater, lesser, and least splanchnic nerves, along with parasympathetic vagal and phrenic inputs. It governs splanchnic perfusion, gastrointestinal motility, adrenal output, and reno-mesenteric tone.

Brainstem hypoperfusion or inflammation impairs vagal efferent tone and promotes sympathetic excess, leading to a dual plexus phenotype. Cardiac plexus dysfunction manifests as inappropriate sinus tachycardia, baroreflex failure, and preload reduction.

Simultaneously, coeliac plexus dysfunction produces excessive splanchnic pooling, orthostatic intolerance, and gastrointestinal dysmotility. These outcomes are compounded by feedback loops involving glial priming, mast cell activation, and peripheral neuropeptide release (e.g., Substance P, CGRP, VIP), which sustain excitatory signalling in both plexuses.

Importantly, the sympathetic chain exhibits anatomical continuity from cervical to thoracic to abdominal levels, allowing pathological signals—such as from vertebral or fascial compression—to propagate bidirectionally across these nodes. Consequently, localized mechanical insult (e.g., T8 vertebral rotation or thoracic outlet obstruction) may produce system-wide dysautonomic effects via convergence on the central-autonomic axis.

1.     TLR4 and Microglial Priming in the Brainstem

TLR4 activation by PAMPs and DAMPs initiates microglial priming and proinflammatory signalling within brainstem autonomic centres such as the NTS, RVLM, and dorsal motor nucleus. This activation leads to the release of cytokines (IL-1β, IL-6, TNF-α), reactive oxygen species (ROS), and nitric oxide, contributing to oxidative stress and synaptic dysfunction. The downstream effect is impaired baroreflex integration, vagal withdrawal, and sympathetic overdrive—central features of autonomic instability in POTS and Long COVID.

Critically, TLR4 signalling interfaces with the RAGE (Receptor for Advanced Glycation End-products) pathway, amplifying inflammatory responses through chronic exposure to AGEs, HMGB1, and S100 proteins. RAGE activation maintains NF-κB signalling and promotes monocyte chemoattractant protein-1 (CCL2) expression, which recruits inflammatory monocytes and primes glial cells within the brainstem. These processes create a self-perpetuating loop of immune sensitization that lowers the threshold for future reactivation.

This same molecular machinery extends to the cardiac and coeliac plexuses. Both contain resident glial-like cells, macrophages, and mast cells that express TLR4 and RAGE. Exposure to systemic DAMPs or local tissue stress (e.g., from mechanical compression or mitochondrial injury) activates these receptors at the plexus level, resulting in neuroinflammation, ganglionic excitability, and impaired autonomic relay.

Thus, the TLR4–RAGE–CCL2 axis acts not only centrally within the brainstem but also peripherally at the nodal autonomic relay points, amplifying dysautonomia across the neuroimmune continuum. TLR4 activation by PAMPs and DAMPs initiates microglial activation, leading to neuroinflammatory signalling (IL-6, TNF-α, ROS) in the NTS, RVLM, and dorsal motor nucleus. This impairs baroreflex sensitivity and disrupts the balance between vagal tone and sympathetic outflow, setting the stage for autonomic instability.

2.     Non-Infectious Triggers of TLR4 Activation: Trauma, Toxins, and Endogenous Stressors

TLR4 is uniquely positioned among pattern recognition receptors to respond not only to pathogen-associated molecular patterns (PAMPs) but also to a broad spectrum of endogenous DAMPs released during cellular stress, tissue injury, and environmental exposures.

Mechanical trauma—including repetitive cervical strain, vertebral rotation, and thoracic outlet compression—can induce the release of extracellular matrix (ECM) breakdown products that act as potent TLR4 ligands, particularly in connective tissue–vulnerable individuals. Environmental toxins such as mould-derived mycotoxins have also been shown to engage TLR4 signalling, often via oxidative stress–mediated pathways and inflammasome crosstalk.

Psychological stress and PTSD—commonly reported in POTS and Long COVID cohorts—amplify TLR4 signalling via stress-induced alarmins such as HMGB1, heat shock proteins, and mitochondrial DNA, which serve as endogenous DAMPs.

This broad spectrum of TLR4 agonists can synergize with RAGE activation and NF-κB–mediated transcriptional amplification, sustaining a hyperinflammatory and neuro-sensitized state.

In genetically predisposed individuals, such persistent activation contributes to glial priming, mitochondrial dysfunction, and immune-mediated autonomic instability, providing a unifying mechanistic link between diverse triggers and the convergent phenotype seen in dysautonomia and central sensitization syndromes.

3.     Dietary Activation of TLR4 and Its Implications in Dysautonomia

Beyond microbial and viral ligands, Toll-like receptor 4 (TLR4) is increasingly recognized as a sensor of dietary-derived damage-associated molecular patterns (DAMPs), particularly in the context of Westernized, high-fat, and high-sugar diets. Saturated fatty acids, such as palmitic acid, and advanced glycation end products (AGEs)—commonly generated during high-temperature cooking—bind to and activate TLR4 either directly or via co-receptors such as CD14 and MD-2.

This dietary activation promotes low-grade systemic inflammation through NF-κB and MAPK signalling, with downstream production of proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) and perpetuation of microglial priming.

In susceptible individuals—especially those with TLR4 or RAGE polymorphisms—chronic TLR4 activation by dietary ligands may establish a feed-forward loop of neuroimmune sensitization. This mechanism plausibly contributes to central sensitization, metabolic inflexibility, autonomic dysfunction, and impaired vagal tone, particularly in patients with POTS and Long COVID.

Notably, such activation may intersect with mitochondrial distress via secondary inhibition of pyruvate dehydrogenase (PDH) and exacerbate GABAergic and amino acid dysregulation already characteristic of these conditions. Thus, dietary modulation represents a clinically modifiable driver of innate immune overactivation within the broader TLR4/RAGE/NF-κB axis.

4.     Viral Persistence and Mitochondrial DAMPs

Even after acute infection, residual viral proteins or low-level viral persistence—particularly from herpesviruses, SARS-CoV-2, and EBV—can chronically stimulate TLR4 either directly or indirectly. Moreover, mitochondrial dysfunction leads to the release of mitochondrial DNA, cardiolipin, and formyl peptides—each potent TLR4 ligands—further compounding neuroimmune activation.   Current research into amino acid profiling implicates lysine/arginine dysfunction as a likely cause of EBV reactivation, via increased arginine-driven lytic cycle induction, impaired T-cell and epigenetic control and potential glutamate-mediated neuroimmune sensitization.(Manoli & Venditti 2016 (35))

5.     Gut Dysbiosis and LPS Translocation

Compromised gut barrier function ("leaky gut")—frequently seen in POTS, MCAS, and chronic fatigue syndromes—permits the translocation of lipopolysaccharides (LPS) from Gram-negative bacteria into the systemic circulation. LPS is one of the most potent TLR4 agonists, and low-grade endotoxemia maintains chronic TLR4/NF-κB activation, particularly in the vagus nerve and brainstem NTS regions.

6.     Ischaemia–Reperfusion Injury

Venous congestion, vertebral venous reflux, and impaired cerebral perfusion, as described in IJV-obstructed and nutcracker-affected patients, can cause transient ischaemia–reperfusion episodes. This process generates reactive oxygen species (ROS) and DAMPs such as peroxiredoxins and oxidized phospholipids, which are recognized by TLR4, thereby linking mechanical-vascular dysfunction to neuroinflammation.

7.     Cold Shock and Heat Shock Proteins (HSPs)

Acute temperature stress, including febrile illness or environmental extremes, induces HSP release. HSP60 and HSP70 act as danger signals and are recognized by TLR4, contributing to systemic inflammation and glial sensitization.

8.     Extracellular Histones and NETs (Neutrophil Extracellular Traps)

In patients with persistent D-dimer elevation and coagulation abnormalities, histone release from damaged cells or NETs can directly activate TLR4. This mechanism is particularly relevant in post-COVID immune thrombotic states and overlaps with our observed fibrin-amyloid persistence model.

1.     Cardiac and Coeliac Plexus Dysfunction

The cardiac plexus integrates cervical sympathetic and vagal inputs to regulate heart rate and vascular tone. Dysfunction manifests as inappropriate sinus tachycardia and preload failure. The coeliac plexus governs splanchnic vasculature, gut motility, and adrenal output, with dysregulation contributing to postprandial hypotension, gastrointestinal symptoms, and splanchnic pooling.

Structural and Mechanical Drivers

The structural basis of dysautonomia involves an interplay between compromised venous and lymphatic outflow, fascial tension, vertebral alignment, and direct neural compression. Thoracic outlet syndrome (TOS), jugular vein compression at C1, and vertebral venous congestion all impede cerebral venous return, raising intracranial pressure and reducing brainstem perfusion. These mechanical impairments disproportionately affect the medullary autonomic centres responsible for regulating downstream sympathetic and parasympathetic output.

Sympathetic fibres arising from the intermediolateral spinal cord (T1–T12) communicate directly with the cardiac and coeliac plexuses. Vertebral rotation—especially at T6–T9—can generate chronic low-grade sympathetic irritation or afferent barrage to the coeliac plexus, sustaining its hyperexcitability. Similarly, cervical instability or repetitive load-bearing (e.g., backpacks, body armour, poor ergonomics) may impair vagal nerve function or disrupt upper sympathetic ganglia, affecting the cardiac plexus and leading to inappropriate sinus tachycardia.

These anatomical and mechanical inputs do not act in isolation; rather, they converge on a vulnerable axis extending from the spinal cord and vertebral venous system through the brainstem to the autonomic plexuses. This axis may be further destabilized by local cytokine release (e.g., IL-6, TNF-α), mast cell degranulation, and neuropeptide-mediated vasodilation or vasospasm. Compression of the thoracic outlet, vertebral venous system, or jugular veins impairs cerebral perfusion and glymphatic drainage, promoting regional hypoxia and immune activation. Repetitive strain from backpack use or vertebral rotation at T8 may chronically irritate sympathetic ganglia, compounding dysregulation.

2.     Gastro-cranial Hydraulic Continuum

Vascular compression syndromes such as Nutcracker and MALS produce downstream effects on venous outflow and abdominal congestion. These disturbances propagate cranially via valveless vertebral venous networks, impacting CSF dynamics and brainstem oxygenation.

3.     Mitochondrial and Metabolic Dysfunction

Hypoxia within the brainstem—whether due to mechanical obstruction or systemic factors—compromises mitochondrial oxidative phosphorylation, particularly in neurons with high energetic demand such as those in the NTS and RVLM. This hypoxic stress activates pyruvate dehydrogenase kinase (PDK), inhibiting PDH activity and shifting metabolism toward anaerobic glycolysis.

In parallel, disruption of the malate-aspartate shuttle and impaired clearance of lactate from the CNS further exacerbate the local pro-inflammatory milieu. Excessive ROS generation under these conditions sustains TLR4 signalling and maintains a state of glial activation and synaptic dysfunction.

These mitochondrial insults have functional consequences at the plexus level. In the cardiac plexus, reduced ATP availability may impair cholinergic and adrenergic neurotransmission, destabilizing heart rate regulation. In the coeliac plexus, impaired mitochondrial function contributes to splanchnic vasodilation, gastrointestinal dysmotility, and adrenal dysregulation. This energy failure synergizes with neuroimmune priming to maintain a chronic dysautonomic state. PDH inhibition and malate-aspartate shuttle defects further impair neuronal energetics under hypoxic conditions. Elevated lactate and ROS exacerbate neuroinflammation, sustaining TLR4 activation and sensitization of autonomic circuits.

4.     Sensitization and Network Plasticity

Once established, this state becomes self-perpetuating. Sensitized circuits within the ANS—particularly at the cardiac and coeliac plexus levels—exhibit exaggerated responses to minor inputs. Central-peripheral feedback loops involving mast cells, cytokines, and neuropeptides maintain a heightened state of reactivity.

Conclusion

Dysautonomia—including POTS, ME/CFS, fibromyalgia, and Long COVID—represents a convergence of immune, metabolic, vascular, and anatomical dysfunctions, rather than an idiopathic or psychogenic disorder. This paper proposes a unifying model wherein sustained TLR4–RAGE–CCL2 activation drives neuroimmune sensitization, mitochondrial collapse (notably PDH inhibition and redox stress), and glial–mast cell–neuropeptide feedback loops, all within the anatomical vulnerability of the brainstem and its downstream autonomic plexuses.

At the heart of this model lies brainstem hypoxia—amplified by venous congestion, structural compression, and impaired glymphatic clearance—which creates a permissive environment for mitochondrial failure, glial activation, and excitatory dominance. The resultant dysregulation affects both the cardiac and coeliac plexuses, producing preload failure, splanchnic pooling, and systemic autonomic instability.

Importantly, this framework explains why patients develop multisystem symptoms following diverse triggers—viral infections, trauma, mould exposure, or vertebral strain—and why these symptoms often persist or relapse. Rather than representing separate diseases, these syndromes can be viewed as phenotypic variants along a shared immunometabolic continuum, shaped by individual genetic polymorphisms, environmental exposures, and anatomical predispositions.

Clinically, this model calls for:

• Targeted therapies that modulate TLR4–RAGE–NF-κB–CCL2 signalling (e.g., LDN, famotidine, ketotifen, nicotinamide).

• Mitochondrial rescue strategies (e.g., PDH support, NAD+ repletion, amino acid correction).

• Structural interventions to restore venous-lymphatic drainage and brainstem perfusion.

• Diagnostic paradigms that incorporate metabolomic, genomic, and vascular imaging markers—moving beyond symptom-based labels toward mechanistic stratification.

  
  

By aligning molecular immunology, metabolic stress, and anatomical dysfunction within a single framework, this model offers a coherent explanation for the heterogeneity and persistence of dysautonomia. It opens the path toward precision diagnostics and mechanism-based therapeutics that can restore autonomic stability, rather than merely suppress symptoms.

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