Elucidating the neuroimmune mechanisms underlying pain and inflammation in autoimmune arthritis

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Abstract Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe joint pain and debilitating inflammatory flares. There are currently no safe and effective treatments that achieve long-term remission, and therefore, RA patients are twice as likely to become chronic opioid users than non-RA pain patients. Maladaptive immune cell function is the underlying cause of RA which leads to joint inflammation and activation of nociceptor sensory neurons that trigger pain. Nociceptors, in turn, can regulate immune responses in tissues via peripheral vesicle release. Joints without sensory innervation are protected from arthritis, underscoring the key role of sensory neurons in controlling both pain and inflammation. Therefore, the neuroimmune axis is an excellent potential avenue, to treat RA. However, our understanding of the diverse sensory neurons and immune cells in the joints, how they interact with each other, and how these interactions change over the course of RA is limited. This proposal is a five-year plan of research, training, and career development focused on studying the role of neuroimmune interactions in RA pain and inflammation. In the two-year mentored phase, I will map the receptor-ligand interactions between sensory neurons and immune cells at a single-cell resolution in healthy and inflamed joints to identify neuroimmune pathways linked to arthritis, and also determine which neurons drive pain in response to immune ligands in arthritis. I will accomplish this by utilizing innovative approaches to construct receptor-ligand cell-cell interactomes, assess pain behavior in mice using machine learning and inhibit nociceptor activity in a spatially and temporally controlled manner. This scientific training will complement the career development activities selected to enhance my skills in scientific communication, leadership, mentorship, and ethics of scientific conduct. The insights and skills gained during this training will guide my research in the independent phase, elucidating how nociceptor-immune interactions contribute to the chronicity of RA. This research will uncover the biological mechanisms of joint inflammation and guide the development of novel neuroimmune-based therapies. I have assembled a diverse group of highly accomplished mentors who will ensure that I receive extensive training in pain neurobiology and in the assessment of sensory neuronal function in mice. My training will be further enhanced by the unique scientific environment of the Harvard Medical School and Boston Children’s Hospital research community, which is geared towards unifying my expertise in immunology and sensory neuroscience and enabling my successful transition into an independent academic position as a pain researcher.