Department of Internal Medicine II, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.
Inflammation. 2020 Jun;43(3):1097-1109. doi: 10.1007/s10753-020-01195-z.
Secretory phospholipase A (sPLA) plays a critical role in the pathogenesis of various inflammatory diseases through production of pro-inflammatory eicosanoids. PLA receptor 1 (PLAR) acts as a clearance receptor for sPLAs. This study examined whether PLAR plays a role in the pathogenesis of experimental autoimmune myocarditis using PLAR-deficient (PLAR KO) mice on a BALB/c background. Autoimmune myocarditis was induced by immunization with murine α-myosin heavy chain. In the immunostaining of PLAR wild-type (WT) myocardium, PLAR and sPLAs were expressed in α-SMA cells and neutrophils, respectively. In immunoblot analyses, tissue from PLAR KO myocardium after immunization had five to tenfold increases in the protein level of sPLA-IB and sPLA-IIA compared with PLAR WT myocardium. However, the mRNA expression levels of these sPLAs were similar in PLAR KO and WT myocardium. Compared with PLAR WT myocardium, PLAR KO myocardium after immunization showed 40% increase in areas affected by infiltration of inflammatory cells, eight to tenfold increase in levels of PGE and TXB, and a threefold increase in number of Th17 cells in heart infiltrates assessed by flow cytometric analysis. Finally, PGE promoted IL-23-induced expansion of Th17 cells in vitro. In conclusion, PLAR-deficiency increased sPLA-IB and sPLA-IIA levels in the myocardium after immunization probably through impaired clearance, leading to increased levels of PGE in the myocardium. Elevated PGE induced Th17 cell expansion, exacerbating myocarditis in PLAR KO mice. Thus, PLAR plays an important role in pathogenesis of experimental autoimmune myocarditis.
分泌型磷脂酶 A（sPLA）通过产生促炎类二十烷酸在各种炎症性疾病的发病机制中起关键作用。PLA 受体 1（PLAR）作为 sPLA 的清除受体发挥作用。本研究通过在 BALB/c 背景下使用 PLAR 缺陷（PLAR KO）小鼠，研究了 PLAR 是否在实验性自身免疫性心肌炎的发病机制中发挥作用。自身免疫性心肌炎通过用鼠α-肌球蛋白重链免疫诱导。在 PLAR 野生型（WT）心肌的免疫染色中，PLAR 和 sPLA 分别在α-SMA 细胞和中性粒细胞中表达。在免疫印迹分析中，与 PLAR WT 心肌相比，免疫后 PLAR KO 心肌的 sPLA-IB 和 sPLA-IIA 蛋白水平增加了五到十倍。然而，这些 sPLAs 的 mRNA 表达水平在 PLAR KO 和 WT 心肌中相似。与 PLAR WT 心肌相比，免疫后 PLAR KO 心肌的炎症细胞浸润面积增加了 40%，PGE 和 TXB 的水平增加了八到十倍，通过流式细胞术分析评估的心脏浸润中的 Th17 细胞数量增加了三倍。最后，PGE 促进了体外 PGE 诱导的 Th17 细胞的扩增。总之，PLAR 缺陷增加了免疫后心肌中 sPLA-IB 和 sPLA-IIA 的水平，可能是通过清除受损导致心肌中 PGE 水平升高。升高的 PGE 诱导 Th17 细胞扩增，加剧了 PLAR KO 小鼠的心肌炎。因此，PLAR 在实验性自身免疫性心肌炎的发病机制中起重要作用。
