Mast-Cell-Derived Proteases Mediate Resolution of Inflammatory Pain in Mice

Immune cells play a critical role regulating the transition from acute to chronic pain, however, while the initiation of inflammatory pain is relatively understood (Ji, 2016), the mechanism behind the resolution is unclear. Mast cells reside in the skin and because of their proximity to sensory nervous, a tight interplay with nociceptors has long been proposed (Hendriksen, 2017; Morellini, 2018; Mittal, 2019). These interactions may be beneficial or detrimental, suggesting their participation in pain modulation. The purpose of this study was to evaluate the contribution of mast cells in inflammatory pain induced by intraplantar injection of Complete Freund Adjuvant (CFA). We compared wild type (WT) and mast cell deficient (Kit^W-sh/W-sh) mice. The lack of mast cells drastically impacted mechanical pain resolution demonstrated by lower paw withdrawal thresholds in response to von Frey filaments compared to the WT. In addition to not recovering from pain, Kit^W-sh/W-sh mice had greater edema and higher levels of nitric oxide. Although the number of mast cells did not change in inflamed skin, interestingly, distinct morphology was detected by high dimensional analysis. Moreover, mast cells proteases 4 (mMCPT4) and 5 (mMCPT5) were significantly upregulated in gene and activity during the resolution phase and the inhibition of these proteases impaired pain resolution. Injection of recombinant mMCPT4 and mMCPT5 significantly improved the resolution of pain. Our findings point toward a protective role of mast cells mediated by the release of proteases.