A recent history of immune cell sex differences in the peripheral nervous system in persistent pain states

• Published in: Brain, behavior, and immunity Vol. 128; pp. 766 - 775
• Main Authors: Ho, Madelene Faye S., Farkas, Olivia, Faria, Andre Vilela, Plemel, Jason R., Kerr, Bradley J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2025
• Subjects: Animals; B-Lymphocytes - immunology; Chronic Pain - immunology; Female; Humans; Inflammation - immunology; Macrophages - immunology; Male; Microglia - immunology; Neuralgia - immunology; Peripheral Nervous System - immunology; Sex Characteristics; T-Lymphocytes - immunology
• ISSN: 0889-1591; 1090-2139; 1090-2139
• DOI: 10.1016/j.bbi.2025.05.004

•Sex differences in neuropathic pain were initially found as “microglia-males” and “T cells-females”.•New neuroimmunology studies expand the roles of macrophages and T cells with varying sex similarities and differences.•Roles of macrophages and T cells are dependent on anatomical level within the peripheral nervous system.•The spectrum of pro-/anti-inflammatory profiles on immune cells depend on neuropathy and sex. Pain is entwined with inflammation, and biological sex often influences mechanisms of the immune system. Due to possible differences in inflammatory mechanisms, women are predisposed to autoimmune diseases and chronic pain. Despite sex as a critical variable in clinical cases of autoimmune conditions and its pain comorbidities, fundamental investigations have long underrepresented female subjects in their studies. Fundamental research in the 2010s, however, identified a binary sex specific mechanism for pain in rodents: male pain is microglia-driven while female pain is T cell-driven. Since then, studies have expanded in neuro-immunology to indicate that the sex differences and immune cells involved in these processes take on more elaborate roles when expanded to other causal modalities and anatomical levels of neuropathic and inflammatory pain. In this mini-review, we highlight updated roles for macrophages, T cells, and B cells in the peripheral nervous system during persistent pain conditions: neuropathic pain and inflammatory pain. We discuss sex similarities and sex differences in these cell types. By parsing out the sex specific roles of immune cells in persistent pain states, we may be better positioned to find immune-based therapies that can effectively target chronic pain in sex-biased autoimmune conditions.