Deficiency of Phospholipase A2 Receptor Exacerbates Autoimmune Myocarditis in Mice

Secretory phospholipase A 2 (sPLA 2 ) plays a critical role in the pathogenesis of various inflammatory diseases through production of pro-inflammatory eicosanoids. PLA 2 receptor 1 (PLA 2 R) acts as a clearance receptor for sPLA 2 s. This study examined whether PLA 2 R plays a role in the pathogene...

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Bibliographic Details
Published in:Inflammation 2020-06, Vol.43 (3), p.1097-1109
Main Authors: Kishi, Hiroki, Yamaguchi, Kazuyuki, Watanabe, Kazuhiro, Nakamura, Kazuto, Fujioka, Daisuke, Kugiyama, Kiyotaka
Format: Article
Language:English
Subjects:
Biomedical and Life Sciences
Biomedicine
Eicosanoids
Flow cytometry
Gene expression
Heart diseases
Helper cells
Immunization
Immunology
Inflammatory diseases
Interleukin 23
Internal Medicine
Leukocytes (neutrophilic)
Lymphocytes T
Myocarditis
Myocardium
Myosin
Original Article
Pathogenesis
Pathology
Pharmacology/Toxicology
Phospholipase A2
Prostaglandin E2
Rheumatology
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Summary:Secretory phospholipase A 2 (sPLA 2 ) plays a critical role in the pathogenesis of various inflammatory diseases through production of pro-inflammatory eicosanoids. PLA 2 receptor 1 (PLA 2 R) acts as a clearance receptor for sPLA 2 s. This study examined whether PLA 2 R plays a role in the pathogenesis of experimental autoimmune myocarditis using PLA 2 R-deficient (PLA 2 R KO) mice on a BALB/c background. Autoimmune myocarditis was induced by immunization with murine α-myosin heavy chain. In the immunostaining of PLA 2 R wild-type (WT) myocardium, PLA 2 R and sPLA 2 s were expressed in α-SMA + cells and neutrophils, respectively. In immunoblot analyses, tissue from PLA 2 R KO myocardium after immunization had five to tenfold increases in the protein level of sPLA 2 -IB and sPLA 2 -IIA compared with PLA 2 R WT myocardium. However, the mRNA expression levels of these sPLA 2 s were similar in PLA 2 R KO and WT myocardium. Compared with PLA 2 R WT myocardium, PLA 2 R KO myocardium after immunization showed 40% increase in areas affected by infiltration of inflammatory cells, eight to tenfold increase in levels of PGE 2 and TXB 2 , and a threefold increase in number of Th17 cells in heart infiltrates assessed by flow cytometric analysis. Finally, PGE 2 promoted IL-23-induced expansion of Th17 cells in vitro . In conclusion, PLA 2 R-deficiency increased sPLA 2 -IB and sPLA 2 -IIA levels in the myocardium after immunization probably through impaired clearance, leading to increased levels of PGE 2 in the myocardium. Elevated PGE 2 induced Th17 cell expansion, exacerbating myocarditis in PLA 2 R KO mice. Thus, PLA 2 R plays an important role in pathogenesis of experimental autoimmune myocarditis.
ISSN:0360-3997
1573-2576
DOI:10.1007/s10753-020-01195-z