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Interleukin 4 inhibits high mobility group box-1 protein-mediated NLRP3 inflammasome formation by activating peroxisome proliferator-activated receptor-γ in astrocytes

Author:
Yao, Xiaolong, Jiang, Qian, Ding, Wei, Yue, Pengjie, Wang, Junwen, Zhao, Kai, Zhang, Huaqiu
Source:
Biochemical and biophysical research communications 2019 v.509 no.2 pp. 624-631
ISSN:
0006-291X
Subject:
Western blotting, astrocytes, caspase-1, fluorescent antibody technique, inflammasomes, interleukin-4, nucleoproteins, transcription factor NF-kappa B
Abstract:
High mobility group box-1 protein (HMGB-1) is one of the most important DAMPs and has been previously shown to promote the formation of the NOD-like receptor with pyrin domain containing-3 (NLRP3) inflammasome in microglia. Interleukin 4 (IL4) is a Th2-derived cytokine that plays a significant role in the function of various immune cells. However, the underlying molecular mechanism by which IL4 signaling antagonizes NLRP3 inflammasome is poorly characterized. In particular, whether IL4 could modulate NLRP3 inflammasome in astrocytes remains unknown. In the present study, we elucidated this phenomenon and the mechanism by which IL4 inhibits HMGB1-mediated NLRP3 inflammasome formation in astrocytes. For this purpose, we cultured and extracted primary astrocytes, setup different concentrations of HMGB1, and used immunofluorescence and western blotting to detect NLRP3 inflammasome formation, including NLRP3, ASC and caspase-1, and signaling changes in the nuclear factor κB (NF-κB). Meanwhile, BAY 11–7082 and IL4 were added with HMGB1 to observe the NLRP3 inflammasome and changes in NF-κB expression. Our data showed that HMGB1 could effectively promote NLRP3 inflammasome formation by activating NF-κB in astrocytes. This effect can be inhibited by BAY 11–7082, a NF-κB inhibitor. Meanwhile, IL4 could activate PPARγ via the STAT6 singling pathway and inhibit NF-κB activation, significantly decreasing formation of the NLRP3 inflammasome complex. Our study demonstrated that the NLRP3 inflammasome complex is also expressed in astrocytes, and IL4 could inhibit HMGB1-mediated NLRP3 inflammasome formation, through negative regulation of NF-κB activity and promotion of PPARγ activation.
Agid:
6263933