The Cardiac Microenvironment Instructs Divergent Monocyte Fates and Functions in Myocarditis

Abstract

SUMMARY Two types of monocytes, Ly6Chi and Ly6Clo, infiltrate the heart in murine experimental autoimmune myocarditis (EAM). We discovered a role for cardiac fibroblasts in facilitating monocyte-to-macrophage differentiation of both Ly6Chi and Ly6Clo cells, allowing these macrophages to perform divergent functions in myocarditis progression. During the acute phase of EAM, IL-17A is highly abundant. It signals through cardiac fibroblasts to attenuate efferocytosis of Ly6Chi monocyte-derived macrophages (MDMs) and simultaneously prevents Ly6Clo monocyte-to-macrophage differentiation. We demonstrated an inverse clinical correlation between heart IL-17A levels and efferocytic receptor expressions in humans with heart failure (HF). In the absence of IL-17A signaling, Ly6Chi MDMs act as robust phagocytes and are less proinflammatory, whereas Ly6Clo monocytes resume their differentiation into MHCII+ macrophages. We propose that MHCII+Ly6Clo MDMs are associated with the reduction of cardiac fibrosis and prevention of the myocarditis sequalae.

Plasminogen activator inhibitor-1 reduces cardiac fibrosis and promotes M2 macrophage polarization in inflammatory cardiomyopathy

“…Bone marrow derived circulating monocytes can differentiate into “classical” inflammatory (M1) and “non-classical” patrolling (M2) monocytes. The expression of the surface proteins CD14 and CD16 in combination with the pan-macrophage marker CD68 can be used to distinguish between these two populations [ 23 ]. However, as it was shown that the majority of heart resident human CD68 + macrophages co-express CD14 in dilated and ischemic cardiomyopathies [ 3 ], we applied CD86 and CD163 as additional markers for M1 and M2 macrophages, respectively [ 5 ].…”

“…These bone marrow derived monocytes can differentiate to classical pro-inflammatory CD14 + CD68 + macrophages (M1 macrophages) or to non-classical immunosuppressive CD16 + CD68 + macrophages (M2 macrophages). This process is highly dependent on the cardiac microenvironment including cytokine and chemokine levels, inflammatory milieu as well as fibroblast presence [ 23 ]. Interestingly, PAI-1 has been suggested to be involved in the regulation of monocyte differentiation in cancer, as it promotes the recruitment and polarization of macrophages towards a M2 phenotype [ 26 ].…”

Considering Cause and Effect of Immune Cell Aging on Cardiac Repair after Myocardial Infarction

“…The first monocyte population to appear is pro-inflammatory Ly6C hi monocytes which differentiate into CCR2 + macrophages. As healing proceeds, Ly6C hi monocytes gives rise to Ly6C lo monocytes which differentiate into macrophages at a lower rate and function primarily as pro-reparative cells and survey endothelial cell health for clearance [45][46][47]. The conversion and survival of Ly6C lo monocytes is controlled by Nuclear receptor subfamily 4 group A member 1 (Nr4a1, aka Nur77) [48,49].…”

GSK3 modulation in acute lung injury, myocarditis and polycystic kidney disease-related aneurysm

“…There is estimated around 20% of patients with myocarditis developing dilated cardiomyopathy (DCM) [92]. Studies indicate that different regulations of monocyte differentiation involve in the cardiac microenvironment of myocarditis patients [93]. Given the autoimmune myocarditis animal model and clinical observations, monocytes and macrophages represent around 75% of migrating cells surrounding the injured myocardium [94].…”

“…A recent study indicated that IL-17 and HMGB1 could aggravate the cardiomyocyte apoptosis and autophagy. Extracellular HMGB1 was reported to cause cardiac remodeling, hypertrophy, reperfusion injury and myocardial fibrosis [92,93]. Since autophagy is regulated by autophagy-related proteins, such as, LC3-II/LC3-I and Beclin-1 [105], the increased ratio of LC3-II to LC3-I and the Beclin-1 expression are of significance in H/R group.…”