Somatosensory regulation of macrophage function during inflammatory pain

Abstract

Abstract Pain is a protective mechanism that alerts the organism against dangerous stimuli, much like the innate immune system. These stimuli range from noxious chemical, mechanical, and thermal stimuli to regional inflammation caused by wounds or infections. During an inflammatory pain condition, such as post-operative skin incision, the inflammatory milieu communicates directly with sensory neurons via signaling molecules to either promote or resolve the sensation of pain. The sensory neurons that initiate pain, nociceptors, release neuropeptides in the tissue they innervate which can act on neighboring immune cells and regulate their function. Here, I investigated how neuropeptides released by nociceptors during inflammatory pain regulate macrophage function. In LPS-activated macrophages, I found that the neuropeptides CGRP and PACAP but not Substance P and Galanin reduced secretion of IL-6 and TNF-α suggesting a neuropeptide-specific effect. Notably, CGRP promoted a reparative macrophage signature, by enhancing the release of IL-10 and the transcription of reparative genes such as Arginase I. When macrophages are only transiently exposed to LPS, they acquire a reparative phenotype. Interestingly, CGRP promoted Arginase I induction even further in these reparative macrophages, suggesting that CGRP could act on reparative as well as inflammatory macrophages to promote an anti-inflammatory milieu. These findings suggest that, during an inflammatory condition, when sensory neurons relay the sensation of pain, they also regulate macrophage function locally by release of CGRP and PACAP. By promoting an anti-inflammatory milieu, CGRP release may accelerate both the healing of tissue injury as well as the resolution of pain.