Recruitment of circulating dendritic cell precursors into the infarcted myocardium and pro-inflammatory response in acute myocardial infarction

Abstract

DC (dendritic cells) play an important role in the immune system. They invade peripheral tissues to detect harmful antigens, inducing a local immune response. Studies suggest that DCPs (dendritic cell precursors) might be reduced in AMI (acute myocardial infarction); however, the reason for their reduction is unknown yet. In the present study, circulating mDCPs (myeloid DCPs), pDCPs (plasmacytoid DCPs), tDCPs (total DCPs) and serum levels of TNFα (tumour necrosis factor α), IL (interleukin)-2, -4, -5, -6, -10 and -12 were analysed by flow cytometry in blood of patients with NSTEMI [non-STEMI (ST-segment elevation myocardial infarction)] (n=44) and STEMI (n=34) compared with controls with excluded CAD (coronary artery disease) (n=45). Post-mortem myocardial specimens of patients with AMI (n=12) and healthy myocardium of accident victims (n=10) were immunostained for mDCs (myeloid dendritic cells) T-cells and macrophages. Compared with controls, in patients with AMI a significant decrease in circulating mDCPs, pDCPs and tDCPs was observed (each P<0.0001). The extent of the decrease was higher in STEMI than NSTEMI patients. Serum levels were significantly higher in patients with AMI compared with controls for IL-6, -10, -12 and TNFα (each P<0.03). Immunostaining revealed significantly higher number of DCs, T-cells and macrophages (each P<0.002) in infarcted than control myocardium. We show that circulating DCPs are significantly reduced in AMI, with a pronounced reduction in STEMI patients. This was accompanied by a significant increase of inflammatory serum cytokines in patients with AMI. Immunohistochemical analysis unravelled that the reduction of circulating DCPs might be due to recruitment into the infarcted myocardium.

The cellular immune system in the post-myocardial infarction repair process

“…In contrast with the large numbers of monocytes and neutrophils, the numbers of circulating mDC and pDC are decreased in patients with AMI at the time of hospital admission if compared with healthy controls and patients with coronary artery disease (CAD) [38,47,65]. Within one week, all DC numbers are again within the normal range …”

“…In mice, DC occur in the infarct area and border zone region at day 3 following AMI and reach peak values at day 7 [34,61,66]. In humans, immunohistochemical stains of myocardial tissue proved that mDC are increased in the myocardium of patients who are deceased because of AMI than in those who died in a traffic accident [38,67]. These mDC formed tight complexes with CD3 + T cells [67], offering circumstantial evidence that, besides the innate immune system, adaptive immunity is implicated in the post-AMI repair process as well.…”

“…"=" cell number is comparable to non-infarcted conditions. [38,65]. The recoveries in circulating DC counts from admission to 14 days after AMI has been related to changes in brain natriuretic peptide and creatine-kinase-MB levels [65].…”

“…Dendritic cells (DC) are mediators of inflammation in diseases such as multiple sclerosis [36], inflammatory bowel syndrome [37], and possibly also in AMI [38]. As shown by Van Gisbergen et al, neutrophil interplay with DC can lead to a T helper (Th) 1 immune response and the generation of excessive inflammatory tissue damage [39].…”

Cellular Pathways of Death and Survival in Acute Myocardial Infarction

“…B-cell infiltration in acute MI leads to production of auto-heart IgM and activation of the classical complement cascade [155]. Dendritic cell precursors are recruited to the infarct site and begin presenting cardiac autoantigens via major histocompatibility complex (MHC) to infiltrating lymphocytes and releases IL-6, IL-10, IL-12, and TNF-α [156,157]. Activation of CD8+ cytotoxic T-cells initiates a cell-mediated autoimmune response against CMs via MHC-restricted killing and also attacks healthy CMs, leading to further CM dysfunction [158].…”