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, Fc?Rs) in RA pathogenesis, however, little is known about their contributions to RA pain. Ours and others' studies have revealed that, Fc?R type I (Fc?RI) is expressed not only in immune cells, but also in a subpopulation of primary sensory neurons. Moreover, Fc?RI crosslinking by IgG-IC directly induces neuronal activation in vitro. We have now generated preliminary data that peripheral IgG-IC/Fc?RI signaling also mediates in vivo hyperactivity of joint sensory neurons and joint pain, but not joint inflammation, in both nave 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 Fc?RI.
In Aim1, we will define which subtypes of joint-innervating sensory neurons express Fc?RI. 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 Fc?RI diminishes such effects. We will also test whether IgG-IC is able to evoke acute joint pain through activation of Fc?RI under nave conditions. In addition, we will generate a conditional Fc?RI knockout mouse line to specifically and unambiguously address the contributions of neuronal Fc?RI in this process.
In Aim 2, we will test whether Fc?RI expression and function are upregulated in DRG in the setting of a murine model of antigen-induced arthritis (AIA). Using global and conditional Fc?RI knockout mice, we will also determine whether Fc?RI 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 Fc?RI 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 Fc?RI 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?RI that cannot be adequately controlled by anti-inflammatory treatments.

Public Health Relevance

Joint pain is a major burden for patients with rheumatoid arthritis and represents a pressing unmet medical need. This proposal is designed to determine how abnormal antibody complexes trigger arthritis pain via an inflammation-independent mechanism. The goal of this work is to provide a new direction for therapeutic strategies to treat arthritis pain associated with immune-related diseases in humans.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Mao, Su-Yau
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Qu, Lintao; Caterina, Michael J (2018) Accelerating the reversal of inflammatory pain with NPD1 and its receptor GPR37. J Clin Invest 128:3246-3249