Identification of NURR1 as a Mediator of MIF Signaling During Chronic Arthritis

Abstract

Elucidation of factors regulating glucocorticoid (GC)sensitivity is required for the development of "steroid-sparing" therapies for chronic inflammatory diseases, including rheumatoid arthritis (RA). Accumulating evidence suggests that macrophage migration inhibitory factor (MIF) counterregulates the GC-induction of anti-inflammatory mediators, including mitogen-activated protein kinase phosphatase 1 (MKP1), a critical mitogen-activated protein kinase signaling inhibitor. This observation has yet to be extended to human disease; the molecular mechanisms remain unknown. We investigated NURR1, a GC-responsive transcription factor overexpressed in RA, as a MIF signaling target. We reveal abrogation by recombinant MIF (rMIF) of GC-induced MKP1 expression in RA fibroblast-like synoviocytes (FLS). rMIF enhanced NURR1 expression, artificial NBRE (orphan receptor DNA-binding site) reporter transactivation, and reversed GC-inhibition of NURR1. NURR1 expression was reduced during experimental arthritis in MIF ؊/؊ synovium, and silencing MIF reduced RA FLS NURR1 mRNA. Consistent with NBRE identification on the MKP1 gene, MKP1 mRNA was reduced in FLS that ectopically express NURR1, and silencing NURR1 enhanced MKP1 mRNA in RA FLS. rMIF enhanced NBRE binding on the MKP1 gene, and the absence of the NBRE prevented NURR1-repressive effects on basal and GC-induced MKP1 transactivation. This study defines NURR1 as a novel MIF target in chronic inflammation and demonstrates a role for NURR1 in regulating the anti-inflammatory mediator, MKP1. We propose a MIF-NURR1 signaling axis as a regulator of the GC sensitivity of

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“…In addition, MIF displays a dominant role in diseases that are characterized by pro-inflammatory pathways, such as the severity of rheumatoid arthritis [20], cardiac dysfunction that is seen in sepsis [21], Crohn’s disease [22], and many different cancers [23-25]. …”

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“…Previous studies have shown that expression of the MAPK-regulating protein, MAPK phosphatase-1 (MKP-1) is inhibited by MIF (32, 54, 55), providing a potential mechanism to explain the effect of MIF deficiency on MAPK phosphorylation. In the present study, MKP-1 mRNA expression in unstimulated MIF −/− macrophages was significantly elevated relative to that in WT cells, an effect which could be eliminated by exposing the cells to recombinant MIF (Fig.…”

Macrophage migration inhibitory factor is essential for osteoclastogenic mechanisms in vitro and in vivo mouse model of arthritis

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