Mast cell chymase modulates IL-33 levels and controls allergic sensitization in dust-mite induced airway inflammation

Mast cells (MCs) are major effector cells contributing to allergic conditions. When activated, they can release large amounts of active proteases, including chymase from their secretory granules. Here we assessed the role of the chymase mouse mast cell protease 4 (mMCP-4) in allergic airway inflammation induced by house-dust mite (HDM) extract. mMCP-4-/-) mice demonstrated elevated airway reactivity and eosinophilia compared with wild-type (WT) animals, suggesting a protective role for mMCP-4 during the late inflammatory phase of the disease. However, mMCP-4 also contributed to the sensitization phase, as indicated by higher levels of serum immunoglobulin E in mMCP-4(-/-) vs. WT mice and higher levels of cytokines secreted by HDM-restimulated mMCP-4(-/-) vs. WT splenocytes. In line with a contribution of mMCP-4 in the early stages of disease, HDM extract directly induced chymase secretion from MCs. The elevated airway and inflammatory responses of mMCP-4(-/-) mice were associated with a profound increase in the levels of interleukin (IL)-33 in the lung tissue. Moreover, WT MCs degraded IL-33 more efficiently than did MCs lacking mMCP-4. Together, our findings identify a protective role of a MC chymase in a physiologically relevant model for airway inflammation and suggest that chymase-mediated regulation of IL-33 can account for this protective function.