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

By C. Klasen, K. Ohl, M. Sternkopf, I. Shachar, C. Schmitz, N. Heussen, E. Hobeika, E. Levit-Zerdoun, K. Tenbrock, M. Reth, J. Bernhagen and O. El Bounkari


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 Ca<sup>2+</sup> 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)

Year: 2014
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Provided by: MPG.PuRe
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