M2 polarization of macrophages: Manipulation of spinal cord injury repair

Spinal cord injury results in lasting sensory and motor dysfunction with limited regenerative capacity. Macrophages play a crucial role in orchestrating secondary pathogenesis and repair mechanisms through polarization dynamics. Following spinal cord injury, these immune cells deploy context-dependent responses via divergent regulatory pathways, mediating phagocytic clearance, inflammatory modulation, and neural tissue remodeling. M1 macrophage polarization exacerbates tissue damage through cytokine storms, reactive oxygen species generation, and subsequent neuronal apoptosis, axonal fragmentation, and glial scarring. Conversely, dominant M2 polarization provides neuroprotection by resolving inflammation and promoting axonal sprouting. Strategic manipulation of macrophage plasticity is a promising frontier in spinal cord injury recovery therapy. This review comprehensively examines the regulatory mechanisms that govern macrophage polarization after spinal cord injury, the functional distinctions between resident microglia and peripheral macrophages, the pathophysiological cascades that occur across injury subtypes, and the emerging interventions that span nanotherapeutics, engineered exosomes, electroactive biomaterials, and photobiomodulation. However, there is still a lack of clinical therapies centered around macrophages due to a lack of human trials targeting macrophage reprogramming and excessive reliance on rodent models without validation in non-human primates. However, given the accelerated development of immunomodulatory biomaterials and the expanding mechanistic insights into polarization pathways, the precision targeting of macrophages warrants prioritized investigation for transformative spinal cord injury therapeutics.