Mast cell-derived chymases are essential for the resolution of inflammatory pain in mice

Abstract Immune cells play a critical role in the transition from acute to chronic pain. However, the role of mast cells in pain remains under-investigated. Here, we demonstrated that the resolution of inflammatory pain is markedly delayed in mast-cell-deficient mice. In response to Complete Freund Adjuvant (CFA), mast-cell-deficient mice showed greater levels of nitric oxide and altered cytokine/chemokine profile in inflamed skin in both sexes. In Wild-Type (WT) mice, the number of mast cell and mast cell-derived chymases; chymase 1 (CMA1) and mast cell protease 4 (MCPT4) increased in the inflamed skin. Inhibiting chymase enzymatic activity delayed the resolution of inflammatory pain. Consistently, local pharmacological administration of recombinant CMA1 and MCPT4 promoted the resolution of pain hypersensitivity and attenuated the upregulation of cytokines and chemokines under inflammation. We identified CCL9 as a target of MCPT4. Inhibition of CCL9 promoted recruitment of CD206 + myeloid cells and alleviated inflammatory pain. Our work reveals a new role of mast cell-derived chymases in preventing the transition from acute to chronic pain and suggests new therapeutic avenues for the treatment of inflammatory pain. Summary Mast cell-derived chymases play an unexpected role in the resolution of inflammatory pain and regulate the immune response. Graphical abstract Mast cells derived chymase MCPT4 degrades CCL9 to promote acute inflammatory pain resolution and prevent chronic pain. CFA-induced inflammation increases mast cells that degranulate and release chymases, like MCPT4 and CMA1, which in turn cleaves cytokines and chemokines such as CCL9. CCL9 cleavage induces the recruitment of CD206 + myeloid cells to promote the resolution of pain and prevent the transition from acute to chronic pain.