Brain‐Derived Neurotrophic Factor Precursor Contributes to a Proinflammatory Program in Monocytes/Macrophages After Acute Myocardial Infarction

Abstract

Background The imbalance of monocyte/macrophage polarization toward the preferential proinflammatory phenotype and a lack of normal inflammation resolution are present in acute myocardial infarction (AMI). Our previous study showed that upregulation of brain‐derived neurotrophic factor precursor (proBDNF) in M2‐like monocytes may contribute to the proinflammatory response in the Stanford type‐A acute aortic dissection. The present study aimed to investigate the role of proBDNF signaling in monocytes/macrophages in the progress of AMI. Methods and Results We observed the upregulation of proBDNF in the proinflammatory monocytes of patients with AMI. The upregulation of proBDNF was also observed in the circulating proinflammatory Ly6C high monocytes and cardiac F4/80 + CD86 + macrophages 3 days after AMI in a mice model. To neutralize proBDNF, the mice subjected to AMI were injected intraperitoneally with a monoclonal anti‐proBDNF antibody. Echocardiography, 2,3,5‐triphenyltetrazolium chloride staining, and positron emission tomography/computed tomography results demonstrate that monoclonal anti‐proBDNF antibody treatment further impaired cardiac functions, increased infarct size, and exacerbated the proinflammatory state. Moreover, the level of proinflammatory Ly6C high in the blood and F4/80 + CD86 + in the heart was further increased in monoclonal anti‐proBDNF antibody mice. RNA sequencing revealed that matrix metalloprotease‐9 protein level was dramatically increased, along with the activated proinflammatory‐related cytokines. Matrix metalloprotease‐9 inhibitor treatment attenuated the deteriorated effect of monoclonal anti‐proBDNF antibody on cardiac function and infarct areas. Conclusions Our study shows that endogenous proBDNF in monocytes/macrophages may exert protective roles in cardiac remodeling after AMI by regulating matrix metalloprotease‐9 activity.

Identification of Immuno-Inflammation-Related Biomarkers for Acute Myocardial Infarction Based on Bioinformatics

“…Third, we tried to investigate the pathogenesis of AMI at the cellular level and observed the differential composition of immune cells between patients with AMI and controls. Previous studies have reported that the percentage of monocytes, particularly proinflammatory monocytes, increases in AMI, 71,72 which is consistent with our study. Particularly, Li et al reported that MMP-9 activity played a pathogenic role in the imbalance of monocytes and macrophages in AMI.…”

“…Particularly, Li et al reported that MMP-9 activity played a pathogenic role in the imbalance of monocytes and macrophages in AMI. 71 It is well established that macrophages participate in the development of atherosclerosis. Macrophages are divided into two polarized subsets: proinflammatory M1 and anti-inflammatory M2 phenotypes.…”

Identification of potential therapeutic targets from bioinformatic analysis of necroptosis and immune infiltration in acute myocardial infarction

“…The different activities of macrophages originate from different subtypes and polarizations, showing a pro-in ammatory phenotype in the early stage and an anti-in ammatory phenotype in the late stage of AMI [29,30]. However, the early in ammatory response of the heart plays a vital role in later cardiac recovery and scar formation [31,32]. Therefore, targeted intervention with macrophages and monocytes may be bene cial for treating injury after AMI.…”

ProBDNF and its receptors in immune-mediated inflammatory diseases: novel insights into the regulation of metabolism and mitochondria

“…Our recent study revealed that endogenous proBDNF in proinflammatory monocytes/macrophages played a protective role by regulating MMP‐9 signaling in acute myocardial infarction (AMI). Administration of mAb-proB skewed monocytes/macrophages into a proinflammatory phenotype after AMI ( 35 ).…”