The role of immune regulation in peripheral nerve regeneration: functions of inflammatory cells and cytokines

Background The regenerative repair following peripheral nerve injury is a complex pathophysiological process in which the immune regulatory network plays a crucial role. Conventional understanding posits that inflammatory responses impede nerve regeneration; however, recent studies reveal that immune reactions constitute a “double-edged sword”: a well-timed and moderate inflammatory response is essential for initiating regeneration, whereas excessive or persistent inflammation deteriorates the regenerative microenvironment and hampers repair. This review systematically elaborates the dynamic responses of the innate and adaptive immune systems after peripheral nerve injury. We focus particularly on the phenotypic switch of macrophages from the pro-inflammatory M1 to the anti-inflammatory/reparative M2 type, the early debris-clearing function of neutrophils, the interactions between T lymphocytes and Schwann cells, as well as the intricate signaling networks formed by cytokines and chemokines. The article delves into how these immune cells and factors precisely regulate key processes in Schwann cells—such as dedifferentiation, proliferation, migration, and myelination-thereby influencing axonal regeneration and functional recovery. Finally, this review prospects the translational potential of optimizing the immune microenvironment by targeting specific immune cells or signaling pathways for treating peripheral nerve injuries. Deciphering these delicate immune regulatory mechanisms will provide a critical theoretical foundation for developing novel immunomodulatory strategies to enhance nerve regeneration. Summary In this review, we outline current understanding of the immune mechanisms underlying peripheral nerve regeneration, spanning from established paradigms to emerging therapeutic approaches, such as targeted immunomodulation, biomaterial-assisted microenvironment reshaping, and adoptive immune cell therapy, all of which represent promising avenues for improving functional recovery after nerve injury. Key Messages The integration of immunology and nerve regeneration research is opening new frontiers for treatment. Harnessing the regenerative potential of the immune system while restraining its detrimental effects—through approaches such as precision modulation of macrophage polarization, neutrophil extracellular trap regulation, and T cell-Schwann cell crosstalk targeting—offers encouraging prospects for overcoming the current challenges in peripheral nerve repair.