Current approaches to targeting TLR4 in RA focus on antibodies that prevent receptor dimerisation, offering blockade of TLR4 activation by a broad range of pathogenic and endogenous ligands.12 13 These antibodies are well tolerated in healthy adults and are currently in phase 2a trials in patients with RA,14 for treatment of TLR4-driven disease defined by serum autoantibody signature.15 Here, we show that targeting a single endogenous TLR4 agonist is sufficient to offer therapeutic benefit in arthritis models. Here, TLR4 is linked to rheumatoid arthritis.