MIF Promotes B Cell Chemotaxis through the Receptors CXCR4 and CD74 and ZAP-70 Signaling

Abstract

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with chemokine-like functions that plays a pivotal role in the pathogenesis of inflammatory diseases by promoting leukocyte recruitment. We showed that MIF promotes the atherogenic recruitment of monocytes and T cells through its receptors CXCR2 and CXCR4. Effects of MIF on B cell recruitment have not been addressed. In this study, we tested the involvement of MIF in B cell chemotaxis and studied the underlying mechanism. We show that MIF promotes primary murine B cell chemotaxis in a dose-dependent manner, comparable to the B cell chemokines CXCL13 and CXCL12. Splenic B cells express CXCR4 and the receptor CD74 but not CXCR2. Inhibition of CXCR4 or CD74 or a genetic deficiency of Cd74 in primary B cells fully abrogated MIF-mediated B cell migration, implying cooperative involvement of both receptors. MIF stimulation of B cells resulted in a rapid increase in intracellular Ca2+ mobilization and F-actin polymerization. Intriguingly, the tyrosine kinase ZAP-70 was activated upon MIF and CXCL12 treatment in a CXCR4- and CD74-dependent manner. Pharmacological inhibition of ZAP-70 resulted in abrogation of primary B cell migration. Functional involvement of ZAP-70 was confirmed by small interfering RNA–mediated knockdown in Ramos B cell migration. Finally, primary B cells from ZAP-70 gene–deficient mice exhibited ablated transmigration in response to MIF or CXCL12. We conclude that MIF promotes the migration of B cells through a ZAP-70–dependent pathway mediated by cooperative engagement of CXCR4 and CD74. The data also suggest that MIF may contribute to B cell recruitment in vivo (e.g., in B cell–related immune disorders).

25 Years On: A Retrospective on Migration Inhibitory Factor in Tumor Angiogenesis

“…Interestingly, while several reports indicate that noncanonical MIF-mediated chemokine receptor activation requires the functional interaction of CXCR2 and/or CXCR4 with MIF's primary cell surface receptor CD74 (31)(32)(33), rhabdomyosarcoma cells were found to not express CD74 (23). This result suggests that outside-in signaling by MIF (and likely D-DT) can proceed using a number of different CD74, CXCR2, CXR4 and/or CXCR7 receptor/coreceptor combinations.…”

The CXCL12/CXCR4 chemokine ligand/receptor axis in cardiovascular disease

“…Furthermore, the CXCL12/CXCR4 axis drives chemotaxis or fugetaxis of T-cells in various pathophysiological settings (Poznansky et al, 2000; Dunussi-Joannopoulos et al, 2002; Fernandis et al, 2003; Okabe et al, 2005; Zhang et al, 2005). Similarly, CXCL12 is able to trigger B-cell chemotaxis in vitro through CXCR4 (Klasen et al, 2014). …”

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).…”