Inhibition of neurokinin B promotes functional recovery in traumatic brain injury by increasing M2 microglia.

Microglial polarization into pro-inflammatory M1 and anti-inflammatory M2 phenotypes is critical for regulating neuroinflammation and tissue repair following traumatic brain injury (TBI). The M1/M2 balance determines neurological outcomes, yet the mechanisms governing this polarization remain unclear. This study identifies neurokinin B (NKB) as a novel regulator of microglial M1/M2 polarization in TBI. Using a murine TBI model, we demonstrated significant upregulation of NKB and its receptor NK3R. Genetic knockdown of NKB enhanced functional recovery and shifted microglial polarization from the detrimental M1 to the beneficial M2 phenotype. Conversely, NKB administration promoted M1 activation while suppressing M2 markers in microglial cultures, potentially through inhibition of the STAT6 pathway. Overexpression of STAT6 reversed NKB's suppressive effects on M2 polarization, while NK3R antagonism with SB222200 promoted M2 polarization and improved functional outcomes. These findings establish NKB signaling as a key modulator of microglial dynamics after TBI, suggesting that targeting this pathway may promote neuroprotective M2 polarization while inhibiting damaging M1 responses. This dual regulation, combined with improved cognitive recovery, positions NKB as a promising target for developing novel TBI therapies aimed at modulating neuroinflammation.