Deficiency of Phospholipase A2 Receptor Exacerbates Autoimmune Myocarditis in Mice

Autor: Hiroki Kishi, Kazuyuki Yamaguchi, Kazuto Nakamura, Kazuhiro Watanabe, Kiyotaka Kugiyama, Daisuke Fujioka
Rok vydání: 2020
Předmět:
Zdroj: Inflammation. 43:1097-1109
ISSN: 1573-2576
0360-3997
DOI: 10.1007/s10753-020-01195-z
Popis: Secretory phospholipase A2 (sPLA2) plays a critical role in the pathogenesis of various inflammatory diseases through production of pro-inflammatory eicosanoids. PLA2 receptor 1 (PLA2R) acts as a clearance receptor for sPLA2s. This study examined whether PLA2R plays a role in the pathogenesis of experimental autoimmune myocarditis using PLA2R-deficient (PLA2R KO) mice on a BALB/c background. Autoimmune myocarditis was induced by immunization with murine α-myosin heavy chain. In the immunostaining of PLA2R wild-type (WT) myocardium, PLA2R and sPLA2s were expressed in α-SMA+ cells and neutrophils, respectively. In immunoblot analyses, tissue from PLA2R KO myocardium after immunization had five to tenfold increases in the protein level of sPLA2-IB and sPLA2-IIA compared with PLA2R WT myocardium. However, the mRNA expression levels of these sPLA2s were similar in PLA2R KO and WT myocardium. Compared with PLA2R WT myocardium, PLA2R KO myocardium after immunization showed 40% increase in areas affected by infiltration of inflammatory cells, eight to tenfold increase in levels of PGE2 and TXB2, and a threefold increase in number of Th17 cells in heart infiltrates assessed by flow cytometric analysis. Finally, PGE2 promoted IL-23-induced expansion of Th17 cells in vitro. In conclusion, PLA2R-deficiency increased sPLA2-IB and sPLA2-IIA levels in the myocardium after immunization probably through impaired clearance, leading to increased levels of PGE2 in the myocardium. Elevated PGE2 induced Th17 cell expansion, exacerbating myocarditis in PLA2R KO mice. Thus, PLA2R plays an important role in pathogenesis of experimental autoimmune myocarditis.
Databáze: OpenAIRE
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