Immune and Inflammatory Networks in Myocardial Infarction: Current Research and Its Potential Implications for the Clinic

Figure 1. Immune inflammatory response within the infarcted heart. (A): Shortly after the onset of myocardial infarction (MI), endogenous damage-associated molecular patterns (DAMPs) released from necrotic cardiomyocytes and other injured cells stimulate surviving resident cells and recruited immune cells to produce inflammatory cytokines, chemokines, and proteases (e.g., interleukin [IL]-1β, C-C motif chemokine ligand 2 [CCL2], and matrix metalloproteinases), which initiate innate immune response. Inflammatory macrophages scavenge dying cardiomyocyte-derived DNA fragments to activate interferon regulatory factor 3 (IRF3)-dependent type I interferon (IFN) signals that enhance infarct inflammation. Cardiac fibroblasts produce and release granulocyte-macrophage colony-stimulating factor (GM-CSF) in response to the engagement of their pattern recognition receptors (PRRs), which not only endows monocytes and macrophages with a pro-inflammatory signature but also stimulates bone marrow hematopoiesis. B cell-derived CCL7 further enhance monocyte accumulation in the infarcted heart. (B): In the later phase of ischemic injury, inflammatory macrophages convert their features to the…

Figure 2. Remote organs contributing to immune and inflammatory networks after myocardial infarction (MI). Bone marrow generates billions of immune cells and supplies them to the injured heart, thereby essentially contributing to the immune inflammatory response after MI. Infarct-derived inflammatory cytokines (e.g., interleukin [IL]-1β), damage-associated molecular patterns (e.g., S100A8), and growth factors (e.g., granulocyte-macrophage colony-stimulating factor [GM-CSF]) as well as increased sympathetic nervous signals stimulate bone marrow hematopoietic stem cell proliferation and immune cell production. Spleen also has stem cells and produces mainly myeloid cells in a process known as extramedullary hematopoiesis. Splenic reservoir monocytes exit the spleen and accumulate in injured tissue depending on angiotensin II signaling during the first day of MI. The miR21/HIF-1α axis in splenic marginal zone B cells is essential for C-C motif chemokine ligand 7 production, thereby promoting inflammatory monocyte mobilization to the infarcted heart. B cells also reside in pericardial adipose tissue where GM-CSF-producing B cells potentially enhance infarct inflammation, whereas IL-10-producing…

Figure 3. Clonal hematopoiesis. As we age, somatic mutations accumulate in bone marrow hematopoietic stem cells, some of which confer a competitive advantage or fitness, leading to clonal expansion of the mutated cells. Consequently, the bone marrow expels clonal descendants of the mutant stem cells into peripheral circulation. In this premalignant condition called clonal hematopoiesis, genes frequently mutated are Tet methylcytosine dioxygenase 2 (TET2), DNA methyltransferase 3 alpha (DNMT3A), addition of sex combs like 1 (ASXL1), and Janus kinase 2 (JAK2), and the somatic mutations confer both increased proliferation capacity and inflammatory signature to the mutated cells, thereby leading to adverse post-infarction heart failure with enhanced inflammation.