Session to Highlight Emerging Pathways in Immune-Induced Exaggerated Pain

Growing evidence suggests that an exaggerated immune response that results in peripheral nerve damage and neovascularization plays a significant role in enhanced pain in rheumatic diseases. Understanding these inflammatory mediators and how they impact pain transmission is necessary to develop novel therapies aimed at these targets.

Novel drivers of immune-induced exaggerated pain will be discussed during Inferno Within: The Role of Sensory Systems in Immune-Induced Exaggerated Pain, which will take place on Monday, Nov. 18, from 1–2:30 p.m. ET in Room 146C of the Walter E. Washington Convention Center and be available on demand within 48 hours for registered ACR Convergence 2024 participants by logging into the meeting website. The data and insights presented will apply to people interested in pain, fibroblast biology, and rheumatoid arthritis (RA).

Dana Orange, MD, the Chapman-Perelman Associate Professor of Clinical Investigation at Rockefeller University, will discuss the disconnect she has observed between the level of pain and the amount of inflammation seen in the joints of patients with RA.

“I grew up in medical school thinking that arthritis pain was caused by inflammation, and I assumed that those would be directly related, but it turns out that’s not true,” she said. “We have some patients who don’t have much inflammation in their joints, but they report a lot of pain, sometimes as much pain as those with robust inflammation.”

Dr. Orange conducted gene expression analysis on this subset of patients to understand what their pain was associated with. She found a group of genes associated with pain that were most robustly expressed by the lining layer of fibroblasts in the synovium. These genes were enriched for neuronal growth pathways and predicted to interact with dorsal ganglion sensory nerves.

“We are onto something with these fibroblasts producing factors that are regulating the growth of nerves,” Dr. Orange said. “I think it is fascinating that there are cells in the joint that are influencing the innervation of the joint.”

Beyond this research, other studies in osteoarthritis, joint synovial fibroblasts, and degenerative disc disease have also shown that fibroblasts from painful sites influence the growth of neurons. Thus, this discovery in RA may also be relevant to those other clinical scenarios.

Murali Prakriya, PhD, Magerstadt Professor of Pharmacology and Medicine at Northwestern Feinberg School of Medicine, will discuss the emerging role of calcium signaling in neuropathic pain.

About half (51%) of the brain’s cells are non-neuronal cells called glial cells, which include astrocytes and microglia. Microglia are the primary immune cell type in the brain that can quickly upregulate cytokine production to modulate the activity of neighboring neurons. Dr. Prakriya has been investigating the underlying signaling pathways in both cell types that drive the production of these inflammatory cytokines.

“Calcium signaling is an important intracellular checkpoint that controls the reactivity of microglia and astrocytes after injury,” he said. “Our RNA-seq and functional assays indicate that calcium signaling positively drives the reactivity of microglia and astrocytes toward reactive (inflammatory) phenotypes. If we conditionally delete the Orai1 calcium channel that contributes to calcium signals in astrocytes or microglia, and in this way block calcium signaling that occurs after an insult or injury, we can prevent the production of inflammatory cytokines that harm the neurons and alter their activity in pathological ways.”

By manipulating this immunological aspect of glial function, it may be possible to develop new ways to treat neuropathic pain in novel non-addictive ways.

Christine Beeton, PhD, Professor of Integrative Physiology at Baylor College of Medicine, will discuss novel peptide Kv1.3 channel blockers for the treatment of RA.