# A novel mechanism of rheumatoid arthritis-associated pain > **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $360,250 ## Abstract Abstract: Joint pain in rheumatoid arthritis (RA) represents a significant health burden. Although RA pain is often thought to result from inflammation, it often persists even after optimal control of inflammation with currently available therapies, indicating the involvement of other non-inflammatory mechanisms. Yet, such mechanisms are largely unknown. The formation of immunoglobulin G immune complex (IgG-IC) in the serum and affected joints is a key feature of RA. Despite extensive biological studies on the role of IgG-IC and its receptors (Fc gamma receptors, FcγRs) in RA pathogenesis, however, little is known about their contributions to RA pain. Ours and others' studies have revealed that, FcγR type I (FcγRI) is expressed not only in immune cells, but also in a subpopulation of primary sensory neurons. Moreover, FcγRI crosslinking by IgG-IC directly induces neuronal activation in vitro. We have now generated preliminary data that peripheral IgG-IC/FcγRI signaling also mediates in vivo hyperactivity of joint sensory neurons and joint pain, but not joint inflammation, in both naïve and arthritic states. The goal of this proposal is therefore to test the hypothesis that IgG-IC drives a noninflammatory component of RA-associated joint pain through direct activation of neuronal FcγRI. In Aim1, we will define which subtypes of joint-innervating sensory neurons express FcγRI. We will also perform in vivo electrophysiological recordings and calcium imaging on DRG neurons in the intact mouse to determine whether IgG-IC excites and or sensitizes specific subtypes of joint sensory afferents and whether genetic knockout of FcγRI diminishes such effects. We will also test whether IgG-IC is able to evoke acute joint pain through activation of FcγRI under naïve conditions. In addition, we will generate a conditional FcγRI knockout mouse line to specifically and unambiguously address the contributions of neuronal FcγRI in this process. In Aim 2, we will test whether FcγRI expression and function are upregulated in DRG in the setting of a murine model of antigen-induced arthritis (AIA). Using global and conditional FcγRI knockout mice, we will also determine whether FcγRI signaling, particularly in neurons, contributes in vivo to neuronal hyperexcitability and chronic joint pain in AIA and whether such any roles are dissociable from effects on inflammation. In Aim 3, we will identify candidate miRNAs that target FcγRI and ask whether they regulate baseline noccieptive responsiveness to IgG-IC, whether they are downregulated in the setting of AIA, and conversely, whether overexpression of these miRNAs can reduce neuronal hyperexcitability and nociceptive behaviors by suppressing FcγRI expression in the AIA model. These studies promise to illuminate a novel mechanism underlying RA-associated pain. If successful, they will significantly impact the field by defining a strong candidate therapeutic target for pain in RA and other autoimmune disorders involving Fc... ## Key facts - **NIH application ID:** 9970197 - **Project number:** 5R01AR072230-04 - **Recipient organization:** JOHNS HOPKINS UNIVERSITY - **Principal Investigator:** Lintao Qu - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $360,250 - **Award type:** 5 - **Project period:** 2017-08-06 → 2022-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9970197 ## Citation > US National Institutes of Health, RePORTER application 9970197, A novel mechanism of rheumatoid arthritis-associated pain (5R01AR072230-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9970197. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*