P-111 - (Poster #111) Neuroimmune Crosstalk in RA: A Molecular Link to Neuropathic Pain

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and destruction. Despite the efficacy of anti-inflammatory therapies, many RA patients continue to experience pain that is disproportionate to clinical or radiographic signs of inflammation. These persistent symptoms are suggestive of neuropathic pain, a maladaptive process involving the somatosensory system. Neuropathic descriptors such as “burning” and “prickling” are frequently reported by RA patients, yet the molecular mechanisms linking inflammation and neuropathic pain remain underexplored. This overlap has significant implications for pain management, as conventional anti-inflammatory or nociceptive analgesics may be insufficient to address the neuropathic component. Identifying key inflammatory mediators that may influence neuropathic signaling could lead to the development of more targeted and effective pain therapies. This project utilized bioinformatic protein interaction analysis to identify novel inflammatory genes potentially bridging this pathophysiologic gap.

Purpose/Objectives:

This study aimed to identify critical gene targets at the intersection of inflammation and neuropathic pain. The objective was to use protein interaction modeling to isolate high value inflammatory mediators that may contribute to persistent neuropathic symptoms in RA. Our goal is to support the development of novel therapeutic targets and inform future experimental design using animal models of RA pain.

 

Methods:

A literature search identified over 150 genes associated with inflammatory, nociceptive, and neuropathic pain. These were entered into the STRING database, which analyzes protein-protein interactions. Genes were clustered based on functional pathways: inflammation, immune response, neuropathic pain, cellular growth, and miscellaneous. From each cluster, the two most highly connected genes were selected for further analysis: TRPV1, SCN10A, IL-10, TLR4, POMC, CCR2, BDNF, COMT, SOD2, and TGFB1. Their interactions were mapped to assess cross-pathway connectivity and infer potential mechanisms by which inflammatory processes might drive neuropathic pain.

 

Results: STRING database modeling demonstrated strong interaction networks among inflammatory and neuropathic genes. BDNF and TRPV1 emerged as key hubs linking inflammatory signaling with central pain processing. BDNF, a neurotrophin associated with neuronal survival and central sensitization, was highly expressed in severe RA and found to decrease in response to anti-TNF therapy, indicating a possible marker of inflammatory-driven neuropathic pain. TRPV1, involved in nociception and heat sensitivity, has been shown to mediate joint afferent responses and contribute to edema in arthritis models. TRPV1 knockout mice demonstrated both reduced pain behavior and less joint destruction. Similarly, IL-10 and TLR4 reflected known cytokine regulation pathways, with TLR4 activation leading to downstream IRF3/7 activity and interferon-β signaling. These findings suggest a convergent model where inflammatory mediators not only perpetuate immune responses but also directly modulate neuronal sensitization and maladaptive pain. The model presents multiple novel gene targets for further exploration in in vivo arthritis models, such as the K/BxN murine serum transfer system. Additional genes of interest include CCR2, which mediates monocyte recruitment and may amplify neuroimmune crosstalk, and TGFB1, a regulator of joint fibrosis and synovial pathology.

Conclusions/Implications for future research and/or clinical care: This study highlights the bioinformatic utility of STRING modeling to identify overlapping mechanisms between inflammation and neuropathic pain in RA. Several key genes particularly BDNF, TRPV1, and TLR4 represent potential mediators of persistent pain that persists despite clinical remission. Future preclinical work should evaluate these genes in knockout mouse models to assess their role in both inflammatory signaling and pain behavior. Clinically, this work supports a paradigm shift in RA pain management: addressing pain as not purely inflammatory, but also as neuropathic. These findings could support the rationale for incorporating neuropathic pain agents (e.g., SNRIs, gabapentinoids) earlier in treatment algorithms. Furthermore, biomarkers like BDNF may offer clinical utility in predicting patients at risk for chronic pain, allowing for earlier and more individualized interventions. Long term, this project contributes to the evolving understanding of neuroimmune interaction in chronic autoimmune diseases and highlights the need for targeted, mechanism based pain therapeutics.