Differential roles of cardiac and leukocyte derived macrophage migration inhibitory factor in inflammatory responses and cardiac remodelling post myocardial infarction

Abstract

Myocardial infarction (MI) provokes regional inflammation which facilitates the healing, whereas excessive inflammation leads to adverse cardiac remodelling. Our aim was to determine the role of macrophage migration inhibitory factor (MIF) in inflammation and cardiac remodelling following MI. Wild type (WT) or global MIF deficient (MIFKO) mice were subjected to coronary artery occlusion. Compared to WT mice, MIFKO mice had a significantly lower incidence of post-MI cardiac rupture (27% vs. 53%) and amelioration of cardiac remodelling. These were associated with suppressed myocardial leukocyte infiltration, inflammatory mediators’ expression, and reduced activity of MMP-2, MMP-9, p38 and JNK MAPK. Infarct myocardium-derived or exogenous MIF mediated macrophage chemotaxis in vitro that was suppressed by inhibition of p38 MAPK or NF-κB. To further dissect the role of MIF derived from different cellular sources in post-MI cardiac remodelling, we generated chimeric mice with MIF deficiency either in bone marrow derived-cells (WTKO) or in somatic-cells (KOWT). Compared to WT and KOWT mice, WTKO mice had reduced rupture risk and ameliorated cardiac remodelling, associated with attenuated regional leukocyte infiltration and expression of inflammatory mediators. In contrast, KOWT mice had delayed healing and enhanced expression of M1 macrophage markers, but diminished expression of M2 markers during the early healing phase. In conclusion, global MIF deletion protects the heart from post-infarct cardiac rupture and remodelling through suppression of leukocyte infiltration and inflammation. Leukocyte-derived MIF promotes inflammatory responses after MI, whereas cardiac-derived MIF affects early but not ultimate healing process.

Inhibition of Macrophage Migration Inhibitory Factor Reduces Diabetic Nephropathy in Type II Diabetes Mice

“…More importantly, recent studies have pointed out an important role of MIF in macrophage accumulation and polarization. For instance, MIF deficiency results in reduced expression of inflammatory mediators (e.g., IL-1β, CCL2, and MMPs) and increased production of anti-inflammatory cytokines (e.g., IL-10) in the lesion area [38]. These findings, together with our data that incubation of macrophage cultures with MIF resulted in increased expression of TNF-α, IL-6, IL-1β, and iNOS, all of which are M1 macrophage markers, suggest an important role of MIF in macrophage polarization to M1.We provided evidence that the modulation of macrophage activation and polarization by MIF is of functional significance: (1) the CM from MIFactivated macrophages caused podocyte damage and EMT of renal tubular cells in vitro, and (2) treatment of db/db mice with ISO-1 resulted in reduced macrophage activation in the diabetic kidney, associated with reduced blood glucose level, albuminuria, ECM accumulation and EMT in vivo.…”

The Role of Inflammation in Myocardial Infarction

“…Once infiltrating leukocytes reach the injured area, they release potent cytokines such as IL-1β and TNF-α, which in turn can stimulate the release of other cytokines like IL-1α/β, IL-6, and IL-8 [110] and drive the inflammatory response. Furthermore, the leukocyte-derived MIF is also another important proinflammatory factor mediating macrophage infiltration and the expression of several inflammatory markers [111], playing crucial roles in a later stage.…”

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

“…Although it generally promotes acute and chronic inflammatory processes, MIF has been demonstrated to also exhibit protective effects during myocardial ischemia/reperfusion injury, especially in the ischemic and early reperfusion phase. Similarly, the role of MIF in cardiac remodeling also appears to be dichotomous 21. On the one hand, MIF promotes postinfarct rupture and remodeling by promoting infiltration of immune cells as well as expression of proinflammatory and fibrosis‐related proteins 21, 22.…”

“…On the one hand, MIF promotes postinfarct rupture and remodeling by promoting infiltration of immune cells as well as expression of proinflammatory and fibrosis‐related proteins 21, 22. On the other hand, MIF depletion has been reported to delay post‐MI healing and to worsen aging‐induced cardiac remodeling and fibrosis in myocardial hypertrophy 21, 23, 24…”