LAUSR

IL‐37 is an anti‐inflammatory member of the IL‐1 family that dampens inflammation associated with many noncommunicable diseases. However, mechanisms of IL‐37 regulation remain understudied. We aimed to investigate the enzymatic cleavage of IL‐37 that potentiates extracellular signalling, as well as pathways of IL‐37 secretion. In human monocytes, mature IL‐37 (mIL‐37) was released following canonical NLRP3 inflammasome activation. The release of IL‐37 was blocked by inhibiting plasma membrane permeability and in gasdermin‐D‐deficient THP‐1 cells. While the cleavage of IL‐37 was found to be constitutive, the release of mIL‐37 was blocked in NLRP3‐deficient THP‐1 cells and by NLRP3 inhibitor MCC950 in THP‐1s and primary human monocytes. IL‐37 secretion also occurred after 18‐h exposure to LPS, independently of the alternative NLRP3 inflammasome. This LPS‐dependent IL‐37 secretion required plasma membrane permeability, but not conventional protein secretion apparatus. Mutagenesis of the suggested caspase‐1 cleavage site (D20) or the proposed alternative cleavage site (V46) did not completely block IL‐37 processing. Therefore, we propose a novel pathway in which IL‐37 is cleaved by caspase‐1‐independent mechanisms and released following canonical and alternative NLRP3 inflammasome triggers by differential pathways.