RAGE: A Central Amplifier in POTS

Dr Graham Exelby May 2025

Introduction

Chronic hypoxia is a powerful initiator of immune dysregulation, neurovascular injury, and systemic coagulopathy, particularly in post-viral and autonomic syndromes such as Long COVID, POTS, and ME/CFS. At the molecular level, hypoxia induces damage-associated molecular pattern (DAMP) release and stabilisation of hypoxia-inducible factor 1-alpha (HIF-1α), which together promote activation of the Receptor for Advanced Glycation End Products (RAGE). RAGE is expressed on microglia, astrocytes, endothelium, and neurons, and serves as a central pattern recognition receptor integrating stress, injury, and immune signals. (Curran & Kopp, 2022. (1))

RAGE (Receptor for Advanced Glycation End Products) acts as a pattern recognition receptor and inflammation amplifier, activated by ligands such as AGEs, S100A8/9, HMGB1, and oxidized phospholipids. In POTS and related dysautonomias, chronic low-grade hypoxia (due to venous congestion or impaired glymphatic clearance) upregulates RAGE expression. Once triggered, RAGE sustains a vicious cycle of inflammation via NF-κB, IL-6, and TNFα, promotes endothelial dysfunction via ROS, and amplifies pain signalling through microglial priming and peripheral nerve sensitization

Of particular relevance is the role of Serum Amyloid A (SAA), a hypoxia-inducible acute phase reactant and potent RAGE ligand, which drives the transition from transient to chronic inflammation. SAA-RAGE activation initiates self-amplifying feedback loops via NF-κB, MAPK, and IL-6/STAT3/NFIL-6 signalling, perpetuating neuroinflammation, endothelial dysfunction, and amyloidogenic clot formation. (Curran & Kopp, 2022. (1)) The downstream impact of these cascades is further exacerbated by specific DNA mutations and amino acid deficiencies affecting mitochondrial phospholipid metabolism, endothelial integrity, and immune regulation.(Vittone & Exelby, 2024 (2))(Exelby 2024 (3))  

This section explores the unified pathophysiology linking hypoxia, RAGE activation, immune-coagulative dysregulation, and genetic vulnerability.

RAGE receptors

RAGE is a multifunctional pattern recognition receptor expressed on microglia, astrocytes, neurons, and vascular endothelial cells, playing a key role in innate immune activation, oxidative stress regulation, and neurovascular homeostasis. While RAGE activation is a normal component of injury response, chronic hypoxia/oxidative stress- driven RAGE overactivation fuels persistent neuroinflammation, autonomic instability, and cognitive dysfunction. 

RAGE receptors are widespread but the astrocytes contain the second highest level of RAGE.  The persistence of hypoxia-driven RAGE activation leads to sustained microglial and astrocytic activation, which recovers more slowly than other RAGE-expressing tissues, perpetuating long-term autonomic and cognitive dysfunction. This section explores the mechanisms of RAGE activation in hypoxia, its impact on neuroimmune sensitization, and the necessity of addressing hypoxic triggers to break the cycle of chronic inflammation and neurodegeneration.   It also described the linking between RAGE and elevated D-Dimers in COVID and also seen in other inflammatory pathways.  

RAGE Ligands and Amplification

RAGE binds a range of ligands:

• Serum Amyloid A (SAA) (Eklund et al,2012 (4)) -an acute phase protein where levels rise dramatically in response to inflammation, infection, or other acute conditions that is primarily synthesized in the liver.  It is an apolipoprotein that binds to lipids, is involved in lipid transport particularly in association with high-density lipoproteins (HDLs). (den Hartigh et al, 2023. (5))  SAA plays a role in regulating both innate and adaptive immunity. (Ye & Sun. 2015 (6))

• Advanced glycation end products (AGEs) (Cross et al. 2024 (7)) Advanced glycation end-products (AGEs) are proteins or lipids that become glycated due to exposure to sugars, implicated in aging and the development of degenerative diseases.(Brown. 2019 (8))

• High mobility group box 1 (HMGB1)- HMGB1 is a non-histone chromatin-associated protein that acts as an alarmin, stimulating sterile immune responses when released from damaged cells. (Rojas et al. 2024 (9))

• S100/calgranulin proteins- These calcium-binding proteins are involved in various inflammatory processes and carcinogenesis when interacting with RAGE. (Rojas et al. 2024 (9))

• Amyloid-β (Cross et al. 2024 (7)) This peptide's interaction with RAGE is particularly relevant in neurodegenerative disorders.

• Extracellular matrix proteins (e.g., laminin, collagen IV) can activate RAGE, potentially contributing to tissue remodelling and fibrosis. (Khan et al. 2017 (10))

Upon ligand binding, RAGE activation initiates a feed-forward loop of NF-κB activation, resulting in sustained inflammation, oxidative stress (via NOX activation), and immune recruitment via chemokines (CCL2, CXCL8/IL-8). SAA-RAGE engagement acts as a central switch from transient to chronic inflammation. (Curran & Kopp, 2022. (1)), (Mohanty et al 2025 (11))

Hypoxia as the Initial Trigger and Continuing Source of Immune Dysfunction

Hypoxia, whether mechanical, inflammatory, or infectious, initiates a HIF-1α–mediated metabolic and immune cascade:

• Upregulates IL-1β, IL-6, TNF-α- These cytokines are critical mediators of inflammation and immune responses, promoting inflammatory pathways and recruiting immune cells to sites of injury or infection. (Castillo-Rodriguez et al. 2022 (12))(Yang et al. 2023 (13))

• Induces COX-2, iNOS, ICAM/VCAM, MMP2/9 - These factors contribute to tissue remodelling, inflammation, and degradation of the extracellular matrix (ECM]. (Yang et al. 2023 (13))

• Drives extracellular matrix (ECM) degradation, particularly collagen IV, a critical BBB and endothelial scaffold is particularly vulnerable to degradation under hypoxic conditions, leading to increased vascular permeability and neuroinflammation.(Wang et al 2018 (14))

• Shifts metabolism via PDH inhibition, glycolytic upregulation, lactate accumulation, and impaired oxidative phosphorylation.  Pyruvate dehydrogenase (PDH) is inhibited under hypoxic conditions, which reduces the conversion of pyruvate to acetyl-CoA. This inhibition limits oxidative phosphorylation, leading to increased reliance on glycolysis for ATP production.  There is an upregulation of glycolytic pathways, resulting in lactate accumulation. This metabolic shift is a survival mechanism for cells under low oxygen conditions but can also lead to acidosis if lactate levels rise excessively. (Exelby 2024.(3)) (Wang et al 2018 (14)) (Copeland et al. 2023 (15))

  
  

Hypoxia-Induced DAMP Cascade

The microvascular ischaemia-hypoxia axis (e.g., from Pelvic Congestion, Nutcracker syndrome, vertebral reflux, or jugular obstruction) becomes not only a source of chronic DAMP release, but also a metabolic choke point that limits tissue recovery and sustains immune recruitment. (Rahal et al, 2011 (16)) (Mao et al. 2024.(17))(Lin et al 2023 (18))

Hypoxic cell stress leads to the release of DAMPs including:

• HMGB1

• S100A8/A9

• Heat shock proteins

• Extracellular matrix fragments (laminin, collagen)

• Mitochondrial debris, including formyl peptides and mtDNA

These DAMPs are potent activators of the innate immune system, for example, HMGB1 is a nuclear protein that, when released extracellularly, acts as a powerful DAMP, activating multiple inflammatory pathways. (Wu et al 2022 (19))

These DAMPs activate:

• TLR4 and RAGE receptors → NF-κB and MAPK

• MAPK pathways (ERK, JNK) → SANF, NFIL-6 transcription

• RAGE expression itself, in a self-perpetuating loop reinforced by SAA, AGEs, and amyloidogenic proteins

These pathways are critical in initiating and sustaining inflammatory responses. The activation of NF-κB and MAPK pathways leads to the production of pro-inflammatory cytokines and chemokines. (Liu et al 2015 (20))

In summary, hypoxia acts as an initial trigger for immune dysfunction through HIF-1α-mediated cascades that upregulate pro-inflammatory cytokines, induce ECM degradation, shift metabolism towards glycolysis, and release DAMPs. This multifaceted response not only initiates but also sustains chronic inflammation, highlighting the critical interplay between metabolic changes and immune dysregulation in various pathological conditions.

Serum Amyloid A (SAA) is the most potent activator of RAGE, surpassing AGEs and HMGB1 in sustained signalling.  SAA is now positioned as the primary amplifier of this RAGE cascade, induced both transcriptionally and translationally by NFIL-6 and HIF-1α, forming a nuclear feedback circuit with IL-6 and TNF-α.

RAGE promotes its own gene transcription, that we believe may be the initiator of the feed forward loop.   Key downstream effects of SAA-RAGE interaction include:

Neurovascular and Amyloidogenic Effects

The neurovascular and amyloidogenic effects of RAGE activation and SAA signalling are significant in the context of neuroinflammation and vascular dysfunction, particularly relevant to conditions like Long COVID and POTS.

RAGE is highly expressed in the brain endothelium and astrocytes. SAA-RAGE signalling may drive glial activation, excitotoxicity (via IL-1β–induced NMDA upregulation), and vascular leakage.

• NMDA receptor sensitization (via IL-1β) → excitotoxicity (Mishra et al. 2012. (21))

• Microglial and astrocyte activation → perpetuation of local inflammation (Carniglia et al. 2017 (22))

• Amyloidogenesis: SAA misfolds into β-sheet-rich fibrils, especially under oxidative stress → neurovascular and parenchymal amyloid deposition. (Gaiser et al 2021 (23))

• Vascular Leakage: RAGE activation disrupts tight junctions (occludin, claudins), compromising the blood-brain barrier (BBB) integrity (Curran & Kopp, 2022. (1))

Chronic RAGE activation by SAA disrupts tight junctions (occludin, claudins), enabling infiltration of peripheral cytokines and immune cells.  SAA’s structural shift into β-sheet fibrils contributes to vascular amyloid deposition, co-localizing with fibrin and complement in hypercoagulable states, and may be reflected in persistent D-Dimer testing commonly seen in Long COVID. (Curran & Kopp, 2022. (1)) (Gaiser et al 2021 (23))

• BBB Breakdown: Matrix metalloproteinases (MMP-2/9) cleave collagen and basal lamina, further compromising BBB integrity and BBB breakdown (Curran & Kopp, 2022. (1))

• Nitrosative Stress: Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) contribute to nitrosative stress and vascular dysregulation. (Curran & Kopp, 2022. (1))

• Immune Cell Infiltration: The compromised BBB allows peripheral cytokines and immune cells to enter the CNS, potentially exacerbating neuroinflammation. (Carniglia et al. 2017 (22))

Fascial & Mast Cell Integration

RAGE activation synergizes with mast cell–fibroblast interactions in fascia-dense zones (suboccipital, thoracic inlet), where hypoxic or mechanical stress increases S100 release. RAGE-driven IL-6 and VEGF promote fibroblast–mast cell crosstalk, perpetuating stiffness and neurovascular compression. This loop may underlie persistent tenderness and proprioceptive dysfunction in POTS patients

Additional neurovascular effects

These may explain some of the persistent symptoms seen in Long COVID and POTS. 

• Neurological symptoms: The combination of excitotoxicity, glial activation, and BBB disruption could contribute to cognitive issues and fatigue reported in Long COVID

• Vascular Dysfunction: The vascular leakage and hypercoagulable state may play a role in the orthostatic intolerance characteristic of POTS

• Chronic Inflammation: The self-perpetuating cycle of inflammation driven by RAGE activation and SAA misfolding could explain the prolonged nature of symptoms in these conditions

Linking RAGE to Coagulopathy and D-Dimers

D-Dimer is a fibrin degradation product and is a sensitive marker for venous thromboembolism. The thromboembolic phenomena is a well recognized problem, best known in pulmonary emboli, but also recognized in venous compressive syndromes that are found in all POTS patients to varying degrees- Thoracic Outlet Syndrome (first noted as Paget-Schroetter Syndrome), Nutcracker and May-Thurner Syndromes.

Long COVID is commonly accompanied by persistent elevation of D-Dimer.   But this finding is not isolated to SARS-activation and is found in other patients with hypoxia/inflammatory/mitochondrial dysfunction, and reflects a picture of chronic systemic inflammation.   

Genetic vulnerabilities include:

• PEMT mutations may impair phospholipid metabolism

• CCL2 polymorphisms can enhance inflammatory response (Cirstoveanu et al. 2023.(49))

• MTHFR variants contributing to elevated homocysteine, increasing thrombosis risk. (Cirstoveanu et al. 2023.(24))(Samii et al. 2023 (25))

RAGE sustains pro-inflammatory loops and contributes to fibrin-amyloid deposition and hypercoagulability.   To link these:

• Hypoxia → DAMPs → RAGE → SAA → Inflammation → Amyloid → D-Dimer elevation

• Coagulation abnormalities → Microvascular dysfunction → Hypoxia

• Elevated D-dimers reflect clot formation around amyloid-rich, degraded ECM (particularly relevant in Long COVID and POTS)

• Further compounded by genetic vulnerability eg PEMT, CCL2, MTHFR

• Chronic  inflammation → Mitochondrial dysfunction → Energy depletion

• Brain dysfunction due to inflammation and microvascular issues.

• Self-sustaining loop that exacerbates symptoms, which explains the persistent symptoms seen in conditions like Long COVID and POTS, including fatigue, cognitive issues, and systemic inflammation

Amino Acid and DNA Mutation Interactions

Amino acid deficiencies can have widespread effects on cellular function, particularly in energy metabolism and neurotransmitter synthesis. In the context of POTS, CFS, and Long COVID, these deficiencies may contribute to fatigue, cognitive issues, and autonomic dysfunction.

Amino acid profiling matched to DNA findings from Dr Vittone in POTS, CFS and Long COVID described in DNA Mutations that Underpin POTS and Long COVID (2) has shown:

• Amino acid deficiencies

• Ethanolamine depletion-critical phospholipid in mitochondrial membranes and endothelium, essential for mitochondrial and endothelial membrane integrity (Basu Ball et al. 2018 (52)). Depletion can lead to:

  • Impaired mitochondrial function and energy production

  • Compromised endothelial cell barrier function

  • Altered cellular signalling and membrane fluidity

• PEMT mutations impairing phospholipid metabolism.  Phosphatidylethanolamine N-methyltransferase (PEMT) is crucial for converting phosphatidylethanolamine to phosphatidylcholine (PC).  (Vance 2013 (26))   PEMT gene mutations can result in:

  • Disrupted phospholipid balance in cell membranes

  • Impaired liver function and lipid metabolism

  • Potential contribution to fatty liver disease and metabolic disorders

• CCL2 driven hyperinflammatory endotheliopathy and  coagulation. CCL2 (also known as MCP-1) is a chemokine that plays a significant role in inflammation and vascular function 

• This may be compounded by MTHFR-associated elevated homocysteine pro-coagulant, disrupts endothelial NO and depletes glutathione, a crucial antioxidant.

Table 1: Elevated D-Dimer -Linking Amino Acids to DNA Mutations

CCL2 and the Brainstem Axis

Dysregulation of CCL2 expression has been implicated in the pathogenesis of various health conditions, including rheumatoid arthritis, fibromyalgia, chronic fatigue, chronic pain syndromes, POTS, connective tissue disease, ADHD , autism, and is a potent activator of mast cells.  Elevated CCL2 can disrupt the function of the NTS and PVN, critical brainstem regions involved in autonomic regulation.  Described in DNA Mutations that Underpin POTS and Long COVID (22)

CCL2 and its receptor CCR2 are expressed in critical central autonomic control centres like the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM.)   This can result in altered sympathetic outflow to cardiovascular organs, changes in blood pressure regulation and disruption of respiratory control. (Elsaafien et al 2019. (27))

The CCL2 Dysregulation appears to play an important role in this cascade:

• Monocyte-Driven Coagulopathy

  • Persistent monocyte infiltration into microvasculature

  • Tissue factor from monocytes initiates coagulation

  • Presence of tissue factor positive monocytes in Long COVID (Ranjbar et al. 2022 (28))

• CCL2 Mutations → Endothelial Dysfunction

  • Contributes to vascular permeability, capillary leak, increased fibrin

  • Prolonged endothelial inflammation and persistent elevated D-Dimer (Park et al. 2024 (29))

• CCL2 and Platelet Hyperreactivity

  • CCL2 cross talk with platelet activation pathways

  • Mutations may cause excessive platelet-monocyte aggravates exacerbation hypercoagulation

The CCL2/CCR2 axis represents a critical link between the immune system, autonomic regulation, and vascular function. Its dysregulation in the brainstem and periphery can lead to a cascade of effects that explain many of the symptoms seen in POTS, Long COVID, and related conditions.

Conclusion

Hypoxia-induced RAGE activation, amplified by Serum Amyloid A and sustained DAMP signalling, represents a critical pathogenic axis in chronic inflammatory and neurovascular syndromes. The persistence of this activation leads to central nervous system sensitisation, blood-brain barrier breakdown, and hypercoagulability. This process is not merely inflammatory but also metabolic and genetic:  DNA mutations in PEMT, CCL2, and related immune-regulatory genes intersect with amino acid deficiencies to impair phospholipid metabolism, mitochondrial resilience, and immune homeostasis.

Importantly, the interaction between hypoxia, RAGE-SAA signalling, and monocyte-driven coagulopathy outlines a self-sustaining loop of inflammation and thrombosis, particularly in syndromes with known autonomic, vascular, and metabolic fragility. Recognition of this integrated pathway not only advances mechanistic understanding but also suggests precise molecular targets for intervention. Addressing upstream hypoxia and its downstream amplification via RAGE-SAA-CCL2 may be essential to breaking the cycle of persistent disease.

The persistence of RAGE signalling may explain why post-infectious and post-inflammatory POTS phenotypes become chronic. Importantly, patients with impaired lymphatic clearance, glymphatic stagnation, or mast cell dysregulation show an exaggerated RAGE response, particularly under hypoxic or mechanically compressed conditions. Therapeutic strategies aimed at RAGE inhibition deserve further exploration in stratified trials.

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