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Central role of PD-L1 in cardioprotection resulting from P2Y4 nucleotide receptor loss
Michael Horckmans1, Esteban Diaz Villamil1, Mariaelvy Bianchini2
1Institute of Interdisciplinary Research, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Free University of Brussels, Brussels, Belgium.
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.
Insights
P2Y4 receptor deficiency in mice enhances anti-inflammatory responses in pericardial fat after heart attack. This suggests P2Y4 is a potential target for novel myocardial infarction therapies.
Area of Science:
- Cardiovascular Biology
- Immunology
- Adipose Tissue Biology
Background:
- Pericardial adipose tissue (PAT) immune function is crucial for post-myocardial infarction (MI) treatment strategies.
- P2Y4 nucleotide receptor deficiency previously showed protection against MI, linked to adiponectin overexpression.
Purpose of the Study:
- To investigate the inflammatory state of PAT in P2Y4-deficient mice following myocardial infarction.
- To elucidate the role of P2Y4 in regulating immune cell infiltration and adipocyte characteristics in the context of cardiac ischemia.
Main Methods:
- Utilized P2Y4 knockout (KO) and P2Y4/adiponectin double KO mouse models subjected to myocardial infarction via left anterior descending artery ligation.
- Analyzed pericardial adipose tissue for adipocyte beiging, PD-L1 expression, leukocyte populations (M2c macrophages, regulatory T cells), and fat-associated lymphoid clusters.
- Administered anti-PD-L1 blocking antibody in P2Y4 KO mice to assess the role of PD-L1 in observed cardioprotective effects.
Main Results:
- P2Y4 deficiency led to adipocyte beiging, increased PD-L1 expression, and a higher infiltration of regulatory leukocytes (M2c macrophages, regulatory T cells) in PAT post-MI.
- These changes correlated with reduced expansion of fat-associated lymphoid clusters.
- The anti-inflammatory effects were dependent on adiponectin, as they were absent in P2Y4/adiponectin double KO mice.
- Blocking PD-L1 abolished the reduction in T cell infiltration and cardiac fibrosis observed in P2Y4 KO mice.
Conclusions:
- P2Y4 receptor regulates PD-L1 and adiponectin expression in PAT, influencing the inflammatory response to myocardial infarction.
- Targeting P2Y4 presents a potential therapeutic strategy for mitigating cardiac inflammation and improving outcomes after MI.
- The study highlights P2Y4's role in modulating adipocyte beiging and regulatory leukocyte accumulation, crucial for post-ischemic cardiac response.
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