Open AccessSoluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis
Author(s) -
Soppert Josefin,
Kraemer Sandra,
Beckers Christian,
Averdunk Luisa,
Möllmann Julia,
Denecke Bernd,
Goetzenich Andreas,
Marx Gernot,
Bernhagen Jürgen,
Stoppe Christian
Publication year - 2018
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.118.009384
Subject(s) - necroptosis , medicine , macrophage migration inhibitory factor , protein kinase b , cardioprotection , cancer research , myofibroblast , immunology , cytokine , signal transduction , microbiology and biotechnology , apoptosis , fibrosis , programmed cell death , myocardial infarction , biology , biochemistry
Background Although macrophage migration inhibitory factor ( MIF ) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD 74, the function of the soluble CD 74 receptor ectodomain ( sCD 74) and its interaction with circulating MIF have not been explored in cardiac disease. Methods and Results Cardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co‐treatment with recombinant MIF and sCD 74 induced cell death ( P <0.001), which was mediated by receptor‐interacting serine/threonine‐protein kinase ( RIP) 1/ RIP 3‐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 sCD 74 and MIF (Ifi44: P =0.011; Irg1: P =0.022; Clec4e: P =0.011). Furthermore, Western blot analysis confirmed the role of sCD 74 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 sCD 74 inhibits MIF ‐mediated survival pathway through the C‐X‐C chemokine receptor 4/ AKT axis, enabling the induction of CD 74‐dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD 74/ MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244). Conclusions These findings suggest that treatment of cardiac myofibroblasts with sCD 74 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 sCD 74/ MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.