Mast Cell Activation as a Driver of Central Sensitization in POTS, Long COVID, and Fibromyalgia

Mechanistic Hypotheses and the Role of Collagenase and RAGE Activation

Dr Graham Exelby May 2025

Abstract

Mast cell activation is increasingly recognized as a central amplifier of neuroimmune dysregulation, autonomic instability, and central sensitization across POTS, Long COVID, fibromyalgia, and ME/CFS.

This paper outlines a mechanistic framework in which mast cells—strategically located at neurovascular, dural, and lymphatic interfaces—initiate and perpetuate a pathological cycle involving glial activation, RAGE (Receptor for Advanced Glycation End Products) signalling, and mitochondrial dysfunction.

Upon activation, mast cells release histamine, tryptase, and cytokines that disrupt astrocytic glutamate transport, activate microglia via PAR and TLR4 signalling, and sensitize NMDA receptors—culminating in glutamate excitotoxicity and persistent post-exertional malaise.

Compounding this neuroinflammatory loop is RAGE-mediated NF-κB activation and SIRT4 inhibition, which drive oxidative stress, ATP depletion, and phospholipid dysregulation. These molecular events are further fuelled by lymphatic and venous congestion—particularly at C1 and the thoracic outlet—resulting in hypoxia-induced mast cell priming. Fascia remodelling and collagen degradation via mast cell–derived MMPs contribute to ECM instability, baroreceptor dysfunction, and mechanical allodynia.

This integrated model—bridging mast cell biology, glial sensitization, venous-lymphatic flow obstruction, and RAGE amplification—explains the multisystem symptomatology of dysautonomia syndromes and their resistance to conventional therapies.

Therapeutic implications include mast cell stabilization, mitochondrial restoration, glutamate clearance, and vascular decompression. These approaches target not only symptom relief but also the underlying neuroimmune-metabolic axis that sustains chronic disease states.

Introduction

Central sensitization (CS) is a key feature in POTS, Long COVID, and fibromyalgia, characterized by persistent pain, hyperalgesia, and autonomic dysregulation. Mast cells (MCs), residing in the dura, perivascular spaces, connective tissues, and gut, play a central role in this process through neuroimmune activation, neurogenic inflammation, and persistent glial sensitization.

This section integrates multiple mechanistic hypotheses linking MC degranulation to CS, with an emphasis on collagenase activity, trauma-induced mast cell activation, neuroimmune cross-talk, and fascia remodelling.

Mast cell activation plays a crucial role in neuroinflammation, glutamate metabolism dysfunction, and impaired clearance, particularly in conditions like POTS, Long COVID, CFS/ME, and fibromyalgia.   Mast cells, particularly in the meninges, gut, and autonomic ganglia, release a range of inflammatory mediators upon activation, that directly impair glutamate clearance, astrocyte function, and neuronal excitability. 

Mast cell activation, neuroinflammation, and mitochondrial dysfunction are central to the pathophysiology of POTS, Long COVID, chronic fatigue syndrome (CFS/ME), and fibromyalgia, driving persistent autonomic instability and neuroimmune dysregulation.

At the core of this pathological cascade lies a self-perpetuating feed-forward loop, where mast cell degranulation, glial activation, and RAGE (Receptor for Advanced Glycation End Products) signalling converge to amplify glutamate excitotoxicity, oxidative stress, and mitochondrial impairment.

Upon degranulation, mast cells release histamine, tryptase, TNF-α, and IL-6, which activate astrocytes and microglia, disrupting glutamate homeostasis. Histamine sensitizes NMDA receptors while downregulating astrocytic glutamate transporters (EAAT1/2), leading to extracellular glutamate accumulation and excitotoxicity.

Meanwhile, tryptase stimulates protease-activated receptors (PARs) on microglia, inducing a pro-inflammatory cascade that includes ROS, TNF-α, and excess glutamate release via system xc⁻. This mast cell–glial crosstalk (Figure 1) triggers mitochondrial dysfunction, impairing ATP production and fuelling further neuroinflammation.

Exacerbating this process is RAGE activation, which acts as a powerful amplifier of chronic inflammation and metabolic failure. RAGE binds Advanced Glycation End Products (AGEs), HMGB1, S100 proteins, and amyloid fibrils, triggering NF-κB activation, cytokine upregulation (TNF-α, IL-1β, IL-6, CCL2), and oxidative stress. This promotes mast cell degranulation, further impairing glutamate clearance and sustaining microglial excitotoxicity. Simultaneously, RAGE-induced SIRT4 inhibition and mitochondrial dysfunction lead to intracellular glutamate buildup, ATP depletion, and phospholipid dysregulation, further locking the system into a state of chronic metabolic failure and excitotoxicity.

This mast cell–glial–RAGE axis represents a critical driver of autonomic dysfunction, post-exertional malaise (PEM), and neurovascular instability, forming the underlying pathophysiological network of dysautonomia syndromes. Disrupting this cycle through mast cell stabilization, mitochondrial restoration (NAD⁺/SIRT4 activation), and glutamate clearance (EAAT upregulation, taurine, aspartate, IVIG) offers a potential avenue for therapeutic intervention in these debilitating conditions.

Mast Cell Activation and Central Sensitization

Mast cell activation syndrome (MCAS) contributes to sensory hypersensitivity, autonomic dysfunction, and immune dysregulation in these conditions:

• MC-Tryptase and Histamine activate sensory neurons, promoting central sensitization.

• MC-Microglia Crosstalk → Sustains neuroinflammation via TNF-α, IL-6, and histamine, perpetuating pain and fatigue.

• Glutamate Excitotoxicity → Impaired astrocytic clearance of glutamate drives pain amplification and cognitive fog.

• Venous congestion-induced hypoxia → Triggers MC degranulation, worsening endothelial instability and autonomic dysfunction.

Trauma-Induced Mast Cell Activation

• Physical Trauma & Dysautonomia: Mechanical trauma, including whiplash and spinal injury, is a common antecedent to POTS and fibromyalgia. These injuries activate mast cells in the dura, perivascular spaces, and connective tissue, leading to peripheral and central sensitization.

• MC Activation via DAMPs (Danger-Associated Molecular Patterns): Cellular debris and ATP released after trauma bind purinergic receptors (P2X7) on MCs, triggering histamine, tryptase, and cytokine release.

• Neurogenic Inflammation: Trauma sensitizes TRPV1/TRPA1 channels on sensory neurons, amplifying substance P and CGRP release, which, in turn, activates MCs. This cycle drives neurogenic inflammation and pain sensitization in fibromyalgia and chronic POTS.

  
  

Mast Cell-Lymphatic-Venous Dysfunction

• Mast Cells and Venous Hypertension in POTS & Long COVID:

  • Chronic venous congestion (IJV obstruction, vertebral reflux, iliac compression) leads to hypoxia and venous stasis, major triggers for mast cell degranulation.

  • Hypoxia-induced RAGE activation promotes endothelial damage and VEGF-dependent vascular permeability, worsening oedema and lymphatic dysfunction.

• Lymphatic Dysfunction and Chronic Inflammation:

  • Lymphatic flow impairment causes the retention of histamine, bradykinin, and inflammatory lipids, leading to excessive interstitial fluid accumulation, tissue inflammation, and increased vascular permeability. This is particularly relevant in POTS-associated vascular leak syndrome, where the failure of lymphatic clearance exacerbates fluid dysregulation, and its crossover with lipoedema where similarities suggest lipoedema is a systemic vascular and metabolic disorder sharing major pathophysiological mechanisms:

  • Endothelial glycocalyx dysfunction

  • MCAS-driven capillary hyperpermeability

  • Lymphatic failure and fluid dysregulation

  • PEMT/phospholipid metabolism impairment

  • Oestrogen-modulated vascular fragility

• Histamine and bradykinin accumulate in the extracellular matrix, sensitizing sensory neurons and contributing to widespread hyperalgesia, neuroinflammation, and orthostatic intolerance.

• Fibrosis-driven lymphatic obstruction leads to sustained mast cell priming via TGF-β and IL-33, further amplifying inflammatory cascades and promoting fibroblast proliferation, resulting in long-term tissue stiffening and interstitial oedema.

• Dysregulated lymphatic drainage leads to delayed clearance of inflammatory mediators, sustaining immune activation and prolonging post-exertional malaise (PEM) in ME/CFS and Long COVID.

• Lymphatic endothelial dysfunction impairs the clearance of fibrin and inflammatory microthrombi, contributing to persistent coagulation abnormalities observed in Long COVID.

PEM, Lymphatic Stasis, and Hypoxic ECM Clearance: A Clinical Paradigm Shift

Emerging clinical evidence indicates that manual lymphatic drainage (MLD) can lead to resolution of post-exertional malaise (PEM) in POTS and Long COVID, suggesting that the hypoxic metabolic by-products responsible for PEM may be sequestered within the extracellular matrix (ECM). This represents a crucial mechanistic advance, repositioning PEM as a reversible phenomenon contingent upon interstitial clearance.

ECM-bound metabolites—likely including lactate, oxidized phospholipids, bradykinin, and glutamate—accumulate under conditions of impaired glymphatic and lymphatic flow, exacerbated by RAGE-mediated microvascular congestion and astrocyte dysfunction. Their removal through strategic fascial and lymphatic decompression supports the hypothesis that PEM is not solely neurochemical but partly mechanical and clearance-dependent.

Restoration of aspartate levels following MLD corroborates this hypothesis, reflecting improved malate-aspartate shuttle efficiency and reduced reliance on anaerobic compensation. This underlines the metabolite traffic jam at the neurovascular-lymphatic interface—a novel therapeutic target.

These findings align with the model of mast cell–glial–RAGE axis dysfunction, where the chronic retention of inflammatory ligands in the ECM leads to peripheral priming and central sensitization. They also support the view that RAGE not only amplifies neuroimmune dysfunction but may act as a sensor for ECM stiffness, glycation, and hypoxic burden, making RAGE both a marker and a modulator of PEM.

Peripheral Mast Cell Activation and Neural Transmission to the CNS

MC Activation by Mechanical, Immune, and Metabolic Stressors  

Mast cells are activated by several triggers relevant to POTS, Long COVID, and fibromyalgia, including:

• Mechanical-driven lymphatic obstruction C1 fascial changes are secondary to mast cell activation, rather than the primary driver of dysfunction, is well-supported by the role of mast cells in neurovascular inflammation.  The mechanically-driven obstruction at C1 then acts as a perpetuator of lymphatic stasis, brainstem hypoperfusion, and metabolic dysfunction, reinforcing:

  • Intracranial congestion and dysautonomia.

  • Neuroimmune sensitization and excitotoxicity.

  • Dysfunctional chylomicron metabolism and phospholipid insufficiency.

• Mechanical stress & trauma:

  • Venous congestion and lymphatic dysfunction → local hypoxia → MC activation

• Fascia remodelling via TGF-β-driven fibroblast activation → increased extracellular matrix stiffness → sustained mechanical MC degranulation

  • Collagenase-mediated ECM degradation → mechanosensory activation → heightened pain perception

• Neurogenic inflammation:

  • Substance P, CGRP, and acetylcholine release from sensory/autonomic neurons → MC degranulation (via NK1, TRPV1, and muscarinic receptors)

• Hypoxia & oxidative stress:

  • Hypoxia-driven HIF-1α activation induces RAGE expression, sustaining MC activation

  • RAGE-inflammasome crosstalk amplifies IL-1β, TNF-α, and histamine release

• Metabolic dysfunction & mitochondrial stress:

  • Elevated lactate (due to impaired malate-aspartate shuttle) → increased extracellular acidity → MC degranulation

  • Aspartate/glutamate imbalance → excitotoxicity-driven MC activation

    
    

Mast Cell-Microglia-Astrocyte Crosstalk in Central Sensitization

Figure 1.Cross-talk between Microglia, Astrocytes and Mast Cells

Interactions and mediators between microglia, astrocytes and mast cells in the brain.  Bidirectional interactions are shown.

Source: Carthy E, Ellender T. Histamine, Neuroinflammation and Neurodevelopment: A Review. Front Neurosci. 2021(1)

Mast cell activation, neuroinflammation, and mitochondrial dysfunction are central to the pathophysiology of POTS, Long COVID, chronic fatigue syndrome (CFS/ME), and fibromyalgia, driving persistent autonomic instability and neuroimmune dysregulation. At the core of this pathological cascade lies a self-perpetuating feed-forward loop, where mast cell degranulation, glial activation, and RAGE (Receptor for Advanced Glycation End Products) signalling converge to amplify glutamate excitotoxicity, oxidative stress, and mitochondrial impairment.

Mast cells, astrocytes, and microglia engage in a neuroinflammatory crosstalk that amplifies glutamate excitotoxicity, mitochondrial dysfunction, and autonomic dysregulation, particularly in conditions like POTS, Long COVID, and CFS/ME.

Upon degranulation, mast cells release histamine, tryptase, TNF-α, and IL-6, which activate astrocytes and microglia, disrupting glutamate homeostasis. Histamine sensitizes NMDA receptors while downregulating astrocytic glutamate transporters (EAAT1/2), leading to extracellular glutamate accumulation and excitotoxicity.

Meanwhile, tryptase stimulates protease-activated receptors (PARs) on microglia, inducing a pro-inflammatory cascade that includes ROS, TNF-α, and excess glutamate release via system xc⁻. This mast cell–glial crosstalk triggers mitochondrial dysfunction, impairing ATP production and fuelling further neuroinflammation.

Exacerbating this process is RAGE activation, which acts as a powerful amplifier of chronic inflammation and metabolic failure. RAGE binds Advanced Glycation End Products (AGEs), HMGB1, S100 proteins, and amyloid fibrils, triggering NF-κB activation, cytokine upregulation (TNF-α, IL-1β, IL-6, CCL2), and oxidative stress. This promotes mast cell degranulation, further impairing glutamate clearance and sustaining microglial excitotoxicity.

Simultaneously, RAGE-induced SIRT4 inhibition and mitochondrial dysfunction lead to intracellular glutamate buildup, ATP depletion, and phospholipid dysregulation, further locking the system into a state of chronic metabolic failure and excitotoxicity.

This mast cell–glial–RAGE axis represents a critical driver of autonomic dysfunction, post-exertional malaise (PEM), and neurovascular instability, forming the underlying pathophysiological network of dysautonomia syndromes. Disrupting this cycle through mast cell stabilization, mitochondrial restoration (NAD⁺/SIRT4 activation), and glutamate clearance (EAAT upregulation, taurine, aspartate, IVIG) offers a potential avenue for therapeutic intervention in these debilitating conditions.

In practical management seeking the source of the underlying hypoxia that provokes the whole cascade remains a primary focus for management.  Remove the source of the hypoxia.

Mast cell/ microglia/astrocyte dysfunction :

• Mast cells Activate Microglia and Drive Neuroinflammation- release IL-6, TNF-α, histamine, and tryptase, which activate microglia via:

• Toll-like receptor 4 (TLR4) signalling: MC-derived cytokines sustain neuroinflammation and pain hypersensitivity.

• Purinergic receptor (P2X7) activation: MC-released ATP binds P2X7, activating the NLRP3 inflammasome.

• RAGE-NFκB amplification loop: MC activation of RAGE increases oxidative stress, perpetuating neuroinflammation.

Mast cell-Astrocyte Cross-Talk in Dysautonomia and Fibromyalgia. 

Astrocytes regulate autonomic function, pain processing, and the glymphatic system, and Mast Cell degranulation disrupts astrocytic glutamate clearance via:

• Histamine-mediated NMDA receptor overactivation.

• Microglial activation and glutamate release.

• Cytokine-driven EAAT downregulation.

• Mitochondrial impairment and oxidative stress.

• This creates a self-perpetuating cycle of excitotoxicity, mitochondrial failure, and autonomic instability with excessive sympathetic activation, impaired vagal tone) central to POTS, Long COVID, and related dysautonomia syndromes

  
  

Fascia, Collagenase, and Chronic Pain

• Mast Cell-Induced Collagen Degradation and Fascial Dysfunction

  • MC degranulation releases matrix metalloproteinases (MMP-1, MMP-8, and MMP-13), leading to collagen degradation and ECM remodelling, explaining fascial changes.

  • Fascial integrity loss leads to:

    • Excessive tissue compliance, vascular laxity, and preload dysfunction (contributing to POTS pathophysiology).

    • Proprioceptive dysregulation and mechanosensory hypersensitivity, exacerbating pain states in fibromyalgia and hypermobile EDS (hEDS)-associated POTS.

• Collagenase-Driven Pain Sensitization via TRPV1 and PAR-2 Activation

• Collagen breakdown products sensitize nociceptors (TRPV1, PAR-2, and ASICs), amplifying pain perception.

• PAR-2 activation by MMPs induces persistent hyperalgesia and neurogenic vasodilation, worsening POTS-related vascular dysregulation.

Conclusion: Mast Cell Activation in Central Sensitization and Dysautonomia Syndromes

This section describes mechanistic framework in which mast cell activation functions as a central amplifier and initiator of neuroimmune dysregulation, central sensitization, and autonomic instability across a spectrum of syndromes, including POTS, Long COVID, fibromyalgia, and ME/CFS.

The convergence of mast cell degranulation, glial activation, and RAGE-driven oxidative signalling establishes a self-perpetuating cycle of glutamate excitotoxicity, mitochondrial dysfunction, and post-exertional neuroinflammation.

Importantly, mast cells are uniquely positioned at the interface of mechanical, immune, and metabolic stress, responding to trauma, venous congestion, hypoxia, and lymphatic dysfunction—each of which are commonly observed in POTS phenotypes. Their release of tryptase, histamine, and cytokines directly impairs astrocytic glutamate transport, endothelial integrity, and fascial compliance, compounding preload dysfunction and sensory hypersensitivity.

Recent clinical findings demonstrate that targeted lymphatic therapy can lead to rapid PEM resolution, providing direct evidence for the role of extracellular metabolite clearance in symptom genesis. These insights demand re-evaluation of PEM not merely as a fixed neuroimmune consequence but as a dynamic and reversible response to ECM congestion and hypoxic load, mediated via mast cell–RAGE signalling and disrupted interstitial flow.

The integration of collagenase-mediated ECM degradation, RAGE amplification, and glial sensitization explains the widespread yet often elusive symptomatology of these disorders. This model also reconciles the structural and biochemical aspects of chronic pain, brain fog, and autonomic lability under a common pathophysiological banner.

From a therapeutic standpoint, this work highlights several intervention points:

• Mast cell stabilization (e.g., cromolyn sodium, quercetin),

• H1/H2 blockade: (eg Telfast/Zyrtec [ketotifen] + Famotidine)

• Glutamate modulation (e.g.,taurine, aspartate repletion)

• Mitochondrial support (e.g., NAD⁺ precursors, SIRT4 activation with Liposomal Nicotinamide Riboside),

• RAGE inhibition (e.g.antioxidants),

• Vascular-lymphatic decompression strategies targeting C1, thoracic outlet, and splanchnic beds.

The mast cell–microglia–RAGE axis underpins central sensitization but also connects connective tissue integrity, autonomic tone, and neurovascular stability—offering a roadmap for both clinical phenotyping and personalized therapeutics.

References:

1.     Carthy E, Ellender T. Histamine, Neuroinflammation and Neurodevelopment: A Review. Front Neurosci. 2021 Jul 14;15:680214. doi: 10.3389/fnins.2021.680214. PMID: 34335160; PMCID: PMC8317266.