The neuroimmune microenvironment of peripheral nerve injury: mechanisms, pathophysiology, and therapeutic implications

The peripheral nervous system has the remarkable capacity for spontaneous regeneration after injury. Despite this inherent capability, clinical outcomes remain poor and are often hallmarked by pathophysiologic neuroma formation and limited neurologic recovery. Inflammation is fundamental for successful regeneration but can propagate pathophysiologic outcomes when aberrantly activated. Although the numerous mechanisms whereby nerve regeneration is derailed into a pathophysiologic state have yet to be established, a growing body of research has elaborated the interplay of neuroimmune interactions in successful nerve regeneration. In this review, we synthesize the current understanding of neuroimmune interactions in traumatic peripheral nerve injury, regeneration, and pathophysiology across three domains: (1) resident immune response; (2) innate immune response; and (3) adaptive immune response. Here, we examine the temporal dynamics of immune cell recruitment, polarization, and functional contributions during Wallerian degeneration and regeneration. We propose potential mechanisms of pathophysiologic regeneration, including failed inflammatory resolution and neuroimmune interactions that sustain maladaptive responses. Finally, we aim to connect these basic science mechanisms to current therapeutic strategies. Specifically, we detail how pharmacologic interventions, cellular therapies, energetic stimulation, and hydrogel or conduir-based approaches may modulate the immune response and shape the microenvironment to improve regenerative outcomes. Collectively, a comprehensive understanding of the bidirectional interactions among neural, immune, and other local cell types within the injury microenvironment is critical for developing strategies to improve nerve regeneration and neurologic outcomes.