Myeloid PD-L1 knockout mice exhibited early-onset cardiac dysfunction, reduced left ventricular ejection fraction, and myocardial inflammation, implicating its role in ICI-associated myocarditis.
Does myeloid-specific PD-L1 deficiency lead to cardiac dysfunction and inflammation in a mouse model?
Myeloid-specific PD-L1 plays a critical role in limiting inflammation and maintaining cardiac integrity, suggesting it as a potential therapeutic target for immune checkpoint inhibitor-associated myocarditis.
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by enhancing antitumor immunity but are associated with immune-related adverse events (irAEs), including myocarditis. While T cell involvement in ICI-associated myocarditis is well established, the contribution of myeloid-specific programmed death-ligand 1 (PD-L1) signaling to cardiac immune regulation remains unclear. To investigate the role of myeloid-specific PD-L1 in maintaining cardiac immune homeostasis. We generated a myeloid-specific PD-L1 conditional knockout (KO) mouse model using LysMCre-driven deletion. Cardiac function was assessed by echocardiography. Immune profiling of cardiac and systemic compartments was performed using flow cytometry, qPCR, ELISA, and histological analyses. In vitro co-culture assays were conducted to assess macrophage–fibroblast (FB) and macrophage-T-cell interactions. Myeloid PD-L1 KO mice exhibited early-onset cardiac dysfunction, reduced left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), and upregulated heart failure markers. Immune profiling revealed systemic and myocardial inflammation, with increased C-C chemokine receptor type 2 (CCR2 ⁺ ) macrophages and activated T cells. Co-culture assays confirmed that PD-L1-deficient myeloid cells enhance T-cell activation, Th17 polarization, and FB-mediated fibrotic gene expression. Myeloid-specific PD-L1 plays a critical role in limiting inflammation and maintaining cardiac integrity. Its deficiency promotes a pro-inflammatory microenvironment, contributing to cardiac dysfunction and implicating it as a key player in ICI-associated myocarditis. These findings identify myeloid PD-L1 as a potential therapeutic target to mitigate immune-mediated cardiotoxicity.
Cora et al. (Mon,) conducted a other in ICI-associated myocarditis. Myeloid-specific PD-L1 conditional knockout was evaluated on Cardiac function and immune profiling. Myeloid PD-L1 knockout mice exhibited early-onset cardiac dysfunction, reduced left ventricular ejection fraction, and myocardial inflammation, implicating its role in ICI-associated myocarditis.
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