Enhanced monocyte recruitment and delayed alternative macrophage polarization accompanies impaired repair following myocardial infarction in C57BL/6 compared to BALB/c mice

Abstract

Summary Activation of the innate immune response following myocardial infarction (MI) is essential for infarct repair. Preclinical models of MI commonly use C57BL/6 mice, which have a type 1‐dominant immune response, whereas other mouse strains such as BALB/c mice have a type 2‐dominant immune response. We compared C57BL/6 and BALB/c mice to investigate whether predisposition towards a proinflammatory phenotype influences the dynamics of the innate immune response to MI and associated infarct healing and the risk of cardiac rupture. MI was induced by permanent coronary artery ligation in 12–15‐week‐old male wild‐type BALB/c and C57BL/6 mice. Prior to MI, C57BL/6 mice had a lower proportion of CD206+ anti‐inflammatory macrophages in the heart and an expanded blood pool of proinflammatory Ly6Chigh monocytes in comparison to BALB/c mice. The systemic inflammatory response in C57BL/6 mice following MI was more pronounced, with greater peripheral blood Ly6Chigh monocytosis, splenic Ly6Chigh monocyte mobilization and myeloid cell infiltration of pericardial adipose tissue. This led to an increased and prolonged macrophage accumulation, as well as delayed transition towards anti‐inflammatory macrophage polarization in the infarct zone and surrounding tissues of C57BL/6 mice. These findings accompanied a higher rate of mortality due to cardiac rupture in C57BL/6 mice compared with BALB/c mice. We conclude that lower post‐MI survival of C57BL/6 mice over BALB/c mice is mediated in part by a more pronounced and prolonged inflammatory response. Outcomes in BALB/c mice highlight the therapeutic potential of modulating resolution of the innate immune response following MI for the benefit of successful infarct healing.

Eosinophil Deficiency Promotes Aberrant Repair and Adverse Remodeling Following Acute Myocardial Infarction

“…Thus, pharmacological depletion of eosinophils in C57BL/6 mice, that have a distinct inflammation and repair phenotype compared with BALB/c mice ( 14 ), confirmed the adverse cardiac remodeling phenotype associated with eosinophil depletion, further supporting a role for eosinophils in post-MI remodeling.…”

“…Both models of eosinophil depletion were accompanied by an increase in adverse structural and functional remodeling, indicating that, despite their low representation relative to neutrophil and macrophages, eosinophils have a key positive impact on myocardial repair and remodeling following their recruitment from the blood. Importantly, this outcome was clear in mice that are more (BALB/c) or less (C57BL/6) skewed toward Th2 immune dominance ( 14 ), showing that the influence of eosinophils is not dependent on mouse strain or immune phenotype. Adverse remodeling was accompanied by an increase in scar size in the myocardium of ΔdblGATA mice relative to WT, despite no difference in the initial ischemia-induced injury.…”

Rapid fall in circulating non‐classical monocytes in ST elevation myocardial infarction patients correlates with cardiac injury

“…For example, Lys6C is highly expressed in murine classical monocytes, but is not found in human monocytes. Furthermore, NC monocytes are a minor sub‐population (~10%) of human monocytes, but a major subset of mouse monocytes, depending on background strain 35 . Thus, there is some caution needed when extrapolating findings found in mouse to the conditions in human.…”

“…Furthermore, NC monocytes are a minor sub-population (~10%) of human monocytes, but a major subset of mouse monocytes, depending on background strain. 35 Thus, there is some caution needed when extrapolating findings found in mouse to the conditions in human. Nevertheless, we observed rapid monocyte margination to the coronary endothelium in the mouse heart at 2 hours post-reperfusion potentially explaining the concomitant fall in circulating monocytes in STEMI patients.…”

Rapid fall in circulating non-classical monocytes in ST elevation myocardial infarction patients correlates with cardiac injury

“…For example, Lys6C is highly expressed in murine classical monocytes, but is not found in human monocytes. Furthermore, NC monocytes are a minor subpopulation (∼10%) of human monocytes, but a major subset of mouse monocytes, depending on background strain 34 . Thus, there is some caution needed when extrapolating findings found in mouse to the conditions in human.…”