Research Article: IL-33 promotes efferocytosis by peritoneal macrophages by a mechanism associated with rapid granulocyte IL-13 production
Abstract:
Resolution of inflammation is an active process that requires efferocytosis, the engulfment of apoptotic cells by macrophages, mediated by receptors such as MerTK. IL-33 is an alarmin that initiates type 2 immune responses, including increased production of IL-13, which promotes MerTK expression. The ability of IL-33 to promote efferocytosis in vivo was examined. Intraperitoneal administration of IL-33 to mice increased local MerTK + macrophage numbers within 48h. MerTK + macrophages were not similarly induced by free mitochondria, an alternative cell damage associated signal. Efferocytotic activity was increased rapidly in response to apoptotic thymocytes in IL-33-treated mice. The established inducer of MerTK expression, IL-13, was detected in peritoneal lavage fluid shortly after IL-33 administration. Peritoneal eosinophils expressed the IL-33 receptor and demonstrated both intracellular IL-13 by flow cytometry and significantly increased Il13 transcript expression following IL-33 treatment. In contrast, neither elevated IL-13 expression nor IL-13 protein secretion was observed in peritoneal lymphocyte populations within the first 6 hours after IL-33 administration. Primary cultures of bone marrow-derived mouse mast cells and eosinophils demonstrated IL-13 protein responses to IL-33 administration within 6 h. Mast cell-deficient Cpa3-Cre; Mcl-1 fl/fl mice had significantly reduced IL-13 levels in the peritoneal cavity 3 hours after IL-33 administration when compared with mast cell-containing littermates. In contrast, IL-33-treated eosinophil-deficient ?dblGATA mice had similar levels of IL-13 at this time point as wild type controls. These data demonstrate that IL-33 promotes MerTK expression, critical for efferocytosis by macrophages, by a process associated with an early rapid local increase in IL-13 production to which mast cells are a substantial early contributor. These findings contribute to our understanding of clinical situations where elevated soluble IL-33 receptor (sST2) and/or lower mast cell numbers are associated with worse clinical outcome.
Introduction:
Inflammation is crucial for responding to infection and tissue trauma and, when properly regulated, is followed by restoration of tissue homeostasis ( 1 , 2 ). Resident immune cells generate multiple mediators such as cytokines, chemokines, and eicosanoids, to promote polymorphonuclear cell recruitment and elimination of pathogens or cell debris ( 3 ). Proper orchestration of inflammation resolution is key, as aberrant mediator or resolution processes can lead to chronic inflammation that can result in fibrosis,…
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