MIF and MIF2 have distinct but synergistic roles in CIA pathogenesis

Abstract

Abstract Rheumatoid arthritis (RA) is a relapsing autoimmune disease with progressive joint destruction. High expression alleles of the cytokine macrophage migration inhibitory factor (MIF) are associated with severe erosive RA. MIF and MIF family member D-dopachrome tautomerase (MIF2) signal through the receptor CD74. Previously we reported on the presence of CD74 expressing effector memory T cells in the collagen-induced arthritis (CIA) mouse model and identified CD74+ T cells in human RA synovium fluid. We studied MIF and MIF2 signaling on CD74+ T cells and inflammatory CD74high MΦ in the CIA model. We observed infiltration of CD74+ T cells (1.7 fold increase, p<0.001) and inflammatory CD74high MΦ (2 fold increase, p<0.001) in the joints of WT mice on day 28 post CIA induction. CD74+ T cell infiltration into paws positively correlated with CIA disease score (r=0.731, p=0.003). CD74+ T cells and CD74high MΦ failed to expand or infiltrate in the paws of Mif−/− mice in CIA. Interestingly, CIA induction in Mif2−/− mice expand CD74+ T cells in lymph nodes (0.5 fold increase, p=0.024), but fail to expand in other secondary lymphoid organs or infiltrate joints. Macrophage precursor Gr1high CD74+ monocytes expand in the spleen (3 fold, p<0.001) and blood (1 fold, p<0.001) of Mif2−/− mice, no change in CD74high MΦ levels is observed. The MIF inhibitor MIF098 ameliorates joint inflammation but did not inhibit the expansion or joint infiltration of CD74+ T cells (2 fold, p<0.001), Gr1high CD74+ monocytes, and CD74high MΦ (0.7 fold, p<0.01). Our findings provide evidence for a pathogenic role of novel MIF responsive CD74+ T cell in RA and suggest separate but crucial roles for both MIF and MIF2 in the development and localization for CD74+ T cells and CD74high MΦ in CIA.