Anti-CTLA-4 m2a Antibody Exacerbates Cardiac Injury in Experimental Autoimmune Myocarditis Mice By Promoting Ccl5-Neutrophil Infiltration.
Ming-Ming WuYan-Chao YangYong-Xu CaiShuai JiangHan XiaoChang MiaoXi-Yun JinYu SunXin BiZi HongDi ZhuMiao YuJian-Jun MaoChang-Jiang YuChen LiangLiang-Liang TangQiu-Shi WangQun ShaoQing-Hua JiangZhen-Wei PanZhi-Ren ZhangPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2024)
The risk for suffering immune checkpoint inhibitors (ICIs)-associated myocarditis increases in patients with pre-existing conditions and the mechanisms remain to be clarified. Spatial transcriptomics, single-cell RNA sequencing, and flow cytometry are used to decipher how anti-cytotoxic T lymphocyte antigen-4 m2a antibody (anti-CTLA-4 m2a antibody) aggravated cardiac injury in experimental autoimmune myocarditis (EAM) mice. It is found that anti-CTLA-4 m2a antibody increases cardiac fibroblast-derived C-X-C motif chemokine ligand 1 (Cxcl1), which promots neutrophil infiltration to the myocarditic zones (MZs) of EAM mice via enhanced Cxcl1-Cxcr2 chemotaxis. It is identified that the C-C motif chemokine ligand 5 (Ccl5)-neutrophil subpopulation is responsible for high activity of cytokine production, adaptive immune response, NF-κB signaling, and cellular response to interferon-gamma and that the Ccl5-neutrophil subpopulation and its-associated proinflammatory cytokines/chemokines promoted macrophage (Mφ) polarization to M1 Mφ. These altered infiltrating landscape and phenotypic switch of immune cells, and proinflammatory factors synergistically aggravated anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. Neutralizing neutrophils, Cxcl1, and applying Cxcr2 antagonist dramatically alleviates anti-CTLA-4 m2a antibody-induced leukocyte infiltration, cardiac fibrosis, and dysfunction. It is suggested that Ccl5-neutrophil subpopulation plays a critical role in aggravating anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. This data may provide a strategic rational for preventing/curing ICIs-associated myocarditis.
Keyphrases
- single cell
- left ventricular
- high fat diet induced
- immune response
- flow cytometry
- diabetic rats
- oxidative stress
- multiple sclerosis
- drug induced
- dendritic cells
- heart failure
- rna seq
- metabolic syndrome
- cell proliferation
- atrial fibrillation
- skeletal muscle
- mouse model
- zika virus
- inflammatory response
- dengue virus
- aedes aegypti