MIF interacts with CXCR7 to promote receptor internalization, ERK1/2 and ZAP‐70 signaling, and lymphocyte chemotaxis

Abstract

Macrophage migration-inhibitory factor (MIF) is a pleiotropic cytokine with chemokine-like functions and is a mediator in numerous inflammatory conditions. Depending on the context, MIF signals through 1 or more of its receptors cluster of differentiation (CD)74, CXC-motif chemokine receptor (CXCR)2, and CXCR4. In addition, heteromeric receptor complexes have been identified. We characterized the atypical chemokine receptor CXCR7 as a novel receptor for MIF. MIF promoted human CXCR7 internalization up to 40%, peaking at 50-400 nM and 30 min, but CXCR7 internalization by MIF was not dependent on CXCR4. Yet, by coimmunoprecipitation, fluorescence microscopy, and a proximity ligation assay, CXCR7 was found to engage in MIF receptor complexes with CXCR4 and CD74, both after ectopic overexpression and in endogenous conditions in a human B-cell line. Receptor competition binding and coimmunoprecipitation studies combined with sulfo-SBED-biotintransfer provided evidence for a direct interaction between MIF and CXCR7. Finally, we demonstrated MIF/ CXCR7-mediated functional responses. Blockade of CXCR7 suppressed MIF-mediated ERK-and zeta-chainassociated protein kinase (ZAP)-70 activation (from 2.1-to 1.2-fold and from 2.5-to 1.6-fold, respectively) and fully abrogated primary murine B-cell chemotaxis triggered by MIF, but not by CXCL12. B cells from Cxcr7 2/2 mice exhibited an ablated transmigration response to MIF, indicating that CXCR7 is essential for MIF-promoted B-cell migration. Our findings provide biochemical and functional evidence that MIF is an alternative ligand of CXCR7 and suggest a functional role of the MIF-CXCR7 axis in Blymphocyte migration.-Alampour-Rajabi, S., El Bounkari, O., Rot, A., Müller-Newen, G., Bachelerie, F., Gawaz, M., Weber, C., Schober, A., Bernhagen, J. MIF interacts with CXCR7 to promote receptor internalization, ERK1/2 and ZAP-70 signaling, and lymphocyte chemotaxis. FASEB J. 29, 4497-4511 (2015). www.fasebj.org

New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model

“…Despite their structural dissimilarities, non-chemokine CKR ligands can trigger signaling pathways similar to those induced by endogenous chemokines, although in some cases they initiate unconventional signaling responses [15, 169, 208–212]. For some, binding and signaling relies on the CKR alone [15], while for others, the CKR operates in tandem with another membrane protein that usually serves as primary receptor [210, 213]. …”

“…More recently, the pseudo-chemokine MIF (macrophage migration inhibitory factor), a pleiotropic and proinflammatory chemotactic cytokine of 12.3 kDa highly expressed by tumor cells, has been identified as a ligand for CXCR2 [209], CXCR4 [169] and ACKR3 [210], inducing ERK1/2 and ZAP-70 signaling and chemotaxis. As with gp120, the binding of MIF to CKRs requires a primary receptor, CD74, a single segment membrane-spanning protein also known as HLA class II histocompatibility antigen gamma chain (Fig 4G).…”

Modeling of both shared and distinct interactions between MIF and its homologue D-DT with their common receptor CD74

“…Upon binding with nM affinity to the CD74/CD44 receptor complex [4, 5], MIF initiates a signaling pathway for sustained activation of ERK1/2 MAPK [5] that ultimately leads to gene transcription and synthesis of pro-inflammatory cytokines and chemokines and increased cell survival and proliferation [6]. In addition to binding to the CD74/CD44 receptor complex, MIF also interacts in a non-cognate manner with CXCR2, CXCR4 and CXCR7 [7–9], triggering trafficking and cell chemotactic responses to the sites of acute and chronic inflammation. The MIF protein has been crystalized and its three-dimensional structure was determined.…”

Toll-like Receptors Regulate MIF Expression in Benign Lymphoepithelial Lesion of the Lacrimal Gland

“…Taken together, these data demonstrate a differentially regulation of MIF expression by TLR7/8 in BLEL and suggested the lymphocytes as one of the main source of the circulating MIF in plasma. MIF biological functions mainly relied on interaction with its receptors CD74, CD44 and CXCR2/4/7 [5,[30][31][32][33]. Given that TLR7/8 activation induced the release of MIF in BLEL primary cells, we thought it could also influence the expression of MIF-related receptors; however, following 24h of exposure to TLR7/8 agonist R848, no significant change was observed ( Figure 4B & 4C).…”