A functional heteromeric MIF receptor formed by CD74 and CXCR4

Schwartz, Verena; Lue, Hongqi; Kraemer, Sandra; Korbiel, Joanna; Krohn, Regina M.; Ohl, Kim; Bucala, Richard; Weber, Christian; Bernhagen, Jürgen

doi:10.1016/j.febslet.2009.07.058

Cited by 188 publications

(173 citation statements)

References 42 publications

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“…MIF‐induced phosphorylation of AKT has previously been demonstrated to depend on CXCR4 and CD74 57, 68. Unlike other G‐protein‐coupled receptors that rapidly internalize following stimulation to terminate signaling,69 CXCR4 exhibits a prolonged stimulatory capacity attributed to endosomal signaling.…”

Section: Discussionmentioning

confidence: 99%

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

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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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.

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Section: Discussionmentioning

confidence: 99%

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

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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“…Surprisingly, U373 MG cells do not express CD74. This suggests that MIF could act by endocytosis, as previously described in NIH3T3 fibroblasts (38) or could use a different cell surface receptor, as CXCR2 and CXCR4, which have recently been identified as functional receptors for the MIF (39,40). We are currently investigating those hypotheses in the U373 MG cell line.…”

Section: Discussionmentioning

confidence: 99%

The Dexamethasone-induced Inhibition of Proliferation, Migration, and Invasion in Glioma Cell Lines Is Antagonized by Macrophage Migration Inhibitory Factor (MIF) and Can Be Enhanced by Specific MIF Inhibitors

Piette

Deprez

Roger

et al. 2009

Journal of Biological Chemistry

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Glioblastomas (GBMs) are the most frequent and malignant brain tumors in adults. Glucocorticoids (GCs) are routinely used in the treatment of GBMs for their capacity to reduce the tumor-associated edema. Few in vitro studies have suggested that GCs inhibit the migration and invasion of GBM cells through the induction of MAPK phosphatase 1 (MKP-1). Macrophage migration inhibitory factor (MIF), an endogenous GC antagonist is up-regulated in GBMs. Recently, MIF has been involved in tumor growth and migration/invasion and specific MIF inhibitors have been developed on their capacity to block its enzymatic tautomerase activity site. In this study, we characterized several glioma cell lines for their MIF production. U373 MG cells were selected for their very low endogenous levels of MIF. We showed that dexamethasone inhibits the migration and invasion of U373 MG cells, through a glucocorticoid receptor (GR)-dependent inhibition of the ERK1/2 MAPK pathway. Oppositely, we found that exogenous MIF increases U373 MG migration and invasion through the stimulation of the ERK1/2 MAP kinase pathway and that this activation is CD74 independent. Finally, we used the Hs 683 glioma cells that are resistant to GCs and produce high levels of endogenous MIF, and showed that the specific MIF inhibitor ISO-1 could restore dexamethasone sensitivity in these cells. Collectively, our results indicate an intricate pathway between MIF expression and GC resistance. They suggest that MIF inhibitors could increase the response of GBMs to corticotherapy. Glioblastomas (GBMs)3 are the most frequent primitive cerebral tumor in adults. These highly invasive cancers are prone to infiltrate the surrounding brain parenchyma at considerable distance from the main tumor mass (1). This unavoidably leads to local recurrence and death despite combined surgery, irradiation, and chemotherapy (2, 3).Glucocorticoids (GCs) are routinely used in the treatment of GBMs as they dramatically reduce the tumor-associated edema. There is growing evidence that GCs also inhibit glioma cell proliferation in vitro and tumor growth in vivo (reviewed in Ref. 4). The capacity of GCs to alter migration and invasion in gliomas has received less attention (5, 6). However, dexamethasone was reported to inhibit cell migration and invasion by opposing epidermal growth factor-induced enhancement of urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor in squamous cell carcinoma cells (7), by modulating matrix metalloproteinase activity in vascular smooth muscle cells (8), by enhancing ␣1␤1 integrin expression in human gastric carcinoma cells (9), and by altering the cytoskeleton of human neurobastoma cells (10). In gliomas, the exact mechanisms of this inhibition are yet largely unknown. Bauman et al. (5) showed that dexamethasone inhibits the migration/ invasion of several glioma cell lines (C6, U251, U373, and A172) and that it enhances the inhibition induced by irradiation. Lin et al. (6) recently showed that dexamethasone decreases matrix me...

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“…Furthermore, the regulation of dendritic cell migration (5) and also the cellular responses to the proinflammatory cytokine macrophage migration inhibitory factor are dependent on CD74 as cell surface receptor (6). Coreceptors such as CD44 (7) or CXCR4 (8) are required to initiate signal transduction following migration inhibitory factor binding to CD74. Interestingly, enhanced expression levels of CD74 have been observed in different forms of malignancies and are positively correlated with increased cellular migration and/or invasion (9)(10)(11).…”

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confidence: 99%

Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells

Hüttl

Kläsener

Schweizer

et al. 2015

The Journal of Immunology

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The invariant chain (CD74), a chaperone in MHC class II–mediated Ag presentation, is sequentially processed by different endosomal proteases. We reported recently that clearance of the final membrane-bound N-terminal fragment (NTF) of CD74 is mediated by the intramembrane protease signal peptide peptidase-like (SPPL)2a, a process critical for B cell development. In mice, SPPL2a deficiency provokes the accumulation of this NTF in endocytic vesicles, which leads to a B cell maturation arrest at the transitional 1 stage. To define the underlying mechanism, we analyzed the impact of SPPL2a deficiency on signaling pathways involved in B cell homeostasis. We demonstrate that tonic as well as BCR-induced activation of the PI3K/Akt pathway is massively compromised in SPPL2a−/− B cells and identify this as major cause of the B cell maturation defect in these mice. Altered BCR trafficking induces a reduction of surface IgM in SPPL2a-deficient B cells, leading to a diminished signal transmission via the BCR and the tyrosine kinase Syk. We provide evidence that in SPPL2a−/− mice impaired BCR signaling is to a great extent provoked by the accumulating CD74 NTF, which can interact with the BCR and Syk, and that impaired PI3K/Akt signaling and reduced surface IgM are not directly linked processes. In line with disturbances in PI3K/Akt signaling, SPPL2a−/− B cells show a dysregulation of the transcription factor FOXO1, causing elevated transcription of proapoptotic genes. We conclude that SPPL2a-mediated processing of CD74 NTF is indispensable to maintain appropriate levels of tonic BCR signaling to promote B cell maturation.

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A functional heteromeric MIF receptor formed by CD74 and CXCR4

Cited by 188 publications

References 42 publications

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

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

The Dexamethasone-induced Inhibition of Proliferation, Migration, and Invasion in Glioma Cell Lines Is Antagonized by Macrophage Migration Inhibitory Factor (MIF) and Can Be Enhanced by Specific MIF Inhibitors

Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells

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