Rheumatoid arthritis (RA) is triggered by inflammatory mediators such as anaphylatoxin C5a and immune-complexes, yet much remains to be learned about the underlying mechanisms. Here, we show that C5a and immune-complexes activate the principal TNFα convertase, TACE, thereby triggering release of TNFα. TACE belongs to the ADAM (a disintegrin and metalloproteinase) family of membrane-anchored metalloproteinases, which have emerged as key regulators of cell-cell interactions. Mice lacking TACE in myeloid cells are protected from inflammatory arthritis in the K/BxN serum transfer model of RA, providing the first genetic evidence for a critical role for TACE in myeloid cells in the pathogenesis of RA. These results support the notion that TACE is an attractive target for treatment of TNFα-dependent pathologies.
Disclosure of Interest None Declared