Solid micro particle mediated sterile type2 inflammation is mediated through cell death and A2b adenosine receptor signaling pathways

Abstract

Sterile solid microparticles (MPs) trigger an innate type 2 inflammatory response dependent on a SYK-BTK-IL33 signaling axis (Nature Materials,18, 289,2019). Inoculation with MPs trigger innate inflammation with influx of neutrophils, eosinophils and alternatively activated macrophages (M2). MPs also trigger cell death in macrophages leading to release of IL33 and the development of a type 2 response with increased IL4,IL5 and IL13 and expression of M2 markers including Arg1, Relmα and Chil3. Blockade of cell death by inhibiting necroptosis (necrox-2) or apoptosis (ZVED-FMK) alone or in combination inhibited the MP mediated release of IL33 by macrophages ex vivo. We also examined the role of adenosine in MP-mediated IL-33 release by inoculating LysMCreA2bfl/flwith MP.MP induced inflammation was blocked in LysMCreA2bfl/fmice compared to LysMCre controls, with significant decreases in type 2 cytokines and IL33. Adoptive transfer of wild type macrophages to LysMCreA2bfl/flrestored the MP-mediated type 2 inflammation. These findings indicate that programmed cell death and A2b receptor signaling pathways play a major role in particulate induced sterile inflammation.