AUTHOR=Horckmans Michael , Diaz Villamil Esteban , Bianchini Mariaelvy , De Roeck Lucas , Communi Didier TITLE=Central role of PD-L1 in cardioprotection resulting from P2Y4 nucleotide receptor loss JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1006934 DOI=10.3389/fimmu.2022.1006934 ISSN=1664-3224 ABSTRACT=

A better understanding of the immune function of pericardial adipose tissue is essential to adapt treatments after myocardial infarction. We showed previously that inactivation of mouse P2Y4 nucleotide receptor induces adiponectin overexpression and protection against myocardial infarction. We investigated here the inflammatory state of pericardial adipose tissue in ischemic P2Y4-deficient mice. We demonstrated that P2Y4-deficient mice displayed adipocyte beiging with increased PD-L1 expression and a higher number of regulatory leukocytes in their pericardial adipose tissue after left anterior descending artery ligation, compared to wild type mice. Effectively, a higher level of anti-inflammatory M2c macrophages and regulatory T cells was observed in pericardial adipose tissue of P2Y4 KO mice and correlated with reduced post-ischemic expansion of fat-associated lymphoid clusters. Interestingly, the anti-inflammatory effects observed in P2Y4 KO mice, were no more observed in P2Y4/adiponectin double KO ischemic mice. Finally, the reduction of T cell infiltration and cardiac fibrosis observed in P2Y4-deficient heart was lost after injection of anti-PD-L1 blocking antibody in ischemic mice. The present study defines P2Y4 as a regulator of PD-L1 and adiponectin, and as a potential target for anti-inflammatory therapies to improve myocardial infarction outcome. The combined effect of P2Y4 loss on adipocyte beiging and regulatory leukocyte increase highlights this nucleotide receptor as an important player in post-ischemic cardiac response.