CD11b Blockade Ameliorates Myocardial Ischemia/Reperfusion Injury by Reducing Neutrophil and Monocyte Infiltration

Background Myocardial ischemia/reperfusion (I/R) injury is a leading cause of myocardial dysfunction and is associated with inflammation, apoptosis, and fibrosis. The integrin subunit ITGAM (also known as CD11b) mainly mediates leukocyte infiltration in the inflammatory process. However, the importance of CD11b in the development of myocardial I/R injury is unclear. The goal of this study is to investigate the role of CD11b + immune cells, particularly neutrophils and macrophages, in mediating myocardial I/R injury and to evaluate the therapeutic potential of CD11b inhibition. Methods Wild‐type mice were administered an anti‐CD11b neutralizing antibody before myocardial I/R surgery. Echocardiography and histological staining were used to evaluate cardiac function and injury, respectively. Inflammatory cells were analyzed by flow cytometry in mice and patients with myocardial infarction who underwent percutaneous coronary intervention. Activated fibroblasts from patients with myocardial infarction were detected by positron emission tomography/computed tomography with a [(18)F]‐labeled fibroblast activation protein inhibitor. Results Our results indicated that CD11b expression and the number of CD45 + CD11b + bone marrow mononuclear cells were dramatically increased in the heart tissues of I/R‐treated mice. Moreover, compared with immunoglobulin G treatment, the pharmacological inhibition of CD11b in mice greatly alleviated cardiac dysfunction, infarct size, myocyte apoptosis, CD11b + neutrophils and macrophage infiltration, cardiac fibrosis and fibroblast activation, accompanied by the inhibition of multiple signaling pathways (Bax, caspase‐3, nuclear factor‐κB, and transforming growth factor‐β/Smad2/3) 3 days after I/R surgery. In addition, the numbers of CD15 + CD11b + neutrophils and CD14 + CD11b + monocytes and the levels of inflammatory cytokines (intercellular adhesion molecule ‐1, vascular adhesion molecule ‐1, interleukin‐1β, and interleukin‐6) as well as the levels of fibroblast activation protein inhibitor in patients with myocardial infarction were also significantly greater than those in normal controls. Conclusions Our data demonstrate that CD11b plays an important role in promoting myocardial I/R injury through multiple signaling pathways and that targeting CD11b may represent a promising option for treating heart I/R injury.