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

Abstract

BackgroundAlthough macrophage migration inhibitory factor (MIF) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD74, the function of the soluble CD74 receptor ectodomain (sCD74) and its interaction with circulating MIF have not been explored in cardiac disease.Methods and ResultsCardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co‐treatment with recombinant MIF and sCD74 induced cell death (P<0.001), which was mediated by receptor‐interacting serine/threonine‐protein kinase (RIP)1/RIP3‐dependent necroptosis (P=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and RT‐qPCR technology revealed a 4‐fold upregulation of several interferon‐induced genes upon co‐treatment of myofibroblasts with sCD74 and MIF (Ifi44: P=0.011; Irg1: P=0.022; Clec4e: P=0.011). Furthermore, Western blot analysis confirmed the role of sCD74 as a modulator of MIF signaling by diminishing MIF‐mediated protein kinase B (AKT) activation (P=0.0197) and triggering p38 activation (P=0.0641). We obtained evidence that sCD74 inhibits MIF‐mediated survival pathway through the C‐X‐C chemokine receptor 4/AKT axis, enabling the induction of CD74‐dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD74/MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244).ConclusionsThese findings suggest that treatment of cardiac myofibroblasts with sCD74 and MIF induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the sCD74/MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.

The Role of Macrophage-Inducible C-Type Lectin in Different Stages of Chronic Liver Disease

“…Heart rate variability is further reduced in patients developing ACLF and can be used to predict disease progression and short-term mortality (45). Interestingly, mincle is also expressed in cardiac tissue (46). We also observed an upregulation of mincle in cardiac tissue in the model of ACLF.…”

“…We also observed an upregulation of mincle in cardiac tissue in the model of ACLF. This may be explained by cell dysfunction, whereby mincle induces necroptosis (46).…”

Cross-kingdom mimicry of the receptor signaling and leukocyte recruitment activity of a human cytokine by its plant orthologs

“…As the yeast CXCR4-transformant experiments also implied a role in the activation of signal transduction, we focused on CXCR4 for subsequent functional studies and next asked whether AtMDLs would also trigger MIF-like CXCR4-facilitated signaling responses in mammalian cells. The MIF-/CXCR4-induced PI3K/Akt signaling cascade is a well-studied MIF-mediated response pathway with physiological-/pathophysiological relevance in human macrophages and T cells, as well as for cancer cell survival (20,48,49). We performed signaling studies in HEK293 cells stably overexpressing CXCR4 (HEK293-CXCR4), fostering appreciable surface expression levels of CXCR4 (Supplementary Figure 4B).…”

“…The MIF/CXCR4 signaling axis controls monocyte, T-cell, and B-cell infiltration in atherosclerosis and other inflammatory conditions (17,19). It also contributes to cancer metastasis, cardiac fibroblast survival, and eosinophil inflammation (20,21).…”

Bioinformatic analysis for the identification of potential gene interactions and therapeutic targets in atrial fibrillation

“…TLR4 has been reported to be related to new-onset atrial fibrillation in acute myocardial infarction [25]. Soppert's study has shown that CXCR4 is involved in myofibroblast necroptosis, which may modulate cardiac remodeling in heart failure [26]. Based on these studies, we speculate that these 3 genes may be a novel target for atrial fibrillation treatment.…”