대식세포의 NLRP3 염증복합체 활성 조절에 관여하는 DPP-4 역할

Abstract

Dipeptidyl peptidase-4 (DPP-4, also known as CD26) cleaves and inactivates several chemokines and cytokines, mediating inflammation and immune function. In immune system, DPP-4 mainly plays a role in T cell activation and co-stimulation and is involved in memory immune-senescence. Here, we hypothesized that DPP-4 may negatively regulate NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in macrophages. To investigate this possibility, the potential function of DPP-4 in regulating lipopolysaccharide (LPS)-induced NLRP3-dependent inflammasome activation in macrophages was examined. To investigate the role of DPP-4 in activation of the NLRP3 inflammasome, LPS-primed bone marrow-derived macrophages (BMDMs) of wild type (WT, C57BL6/J) and DPP-4 knockout (KO) mouse were challenged with adenosine triphosphate (ATP). IL-1β and IL-18 expressions were evaluated by immunoblot and enzyme-linked immunosorbent assay (ELISA) assay in cell lysates and supernatants, respectively. We observed that deficiency of DPP-4 in macrophages promotes NLRP3 inflammasome activation. Furthermore, the release of IL-1β and IL-18 proteins in peritoneal lavage fluid were compared between WT and DPP-4 KO mice by ELISA in LPS-induced sepsis model. M1 macrophage-related gene expression of peritoneal macrophage from these mice was analyzed by qRT-PCR. DPP-4 deficiency enhanced the secretion of IL-1β and IL-18 into peritoneal lavage and augmented the transcript levels of macrophage-related genes. Thus, our findings suggest that DPP-4 negatively regulates activation of NLRP3 inflammasomes in vitro, and LPS-induced sepsis model in vivo, by promoting M1 macrophage profile.