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The cytokine TNF-α is a major drug target for rheumatoid arthritis, an inflammatory joint disorder. An alternative approach is to target the protease TNF-α convertase (TACE), which releases TNF-α from cells. However, because TACE cleaves other proteins involved in development and cancer, a tissue-specific inhibition of TACE in immune cells appears mandatory. In this issue of the JCI, Issuree et al. report that iRHOM2 is a TACE activator in immune cells. Loss of iRHOM2 largely protects mice from inflammatory arthritis, making iRHOM2 a potential drug target for this condition.

iRHOM2 takes control of rheumatoid arthritis