UC San Diego

Rheumatoid arthritis (RA) is a chronic autoimmune disorder of the joints. In K/BxN arthritis, disease is mediated by autoantibodies directed toward glucose 6-phosphate isomerase (G6PI). It is currently believed that G6PI is deposited on the joint cartilage where it facilitates autoantibody-mediated attack. This model is heavily dependent on the recruitment of neutrophils in order to contribute to the inflammatory phenotype. We investigated the role of I kappa B kinase epsilon, a non-canonical activator of NF-[kappa]B, in the absence of an interferon response in the pathogenesis of RA. Arthritis in Ikbke-/- mice is attenuated and is characterized by reduced levels of pro-inflammatory cytokines and neutrophil-recruiting chemokines in the joints. Interestingly, these mice are sensitized to therapeutic doses of interferon therapy, which to date has not shown efficacy at reasonable doses in human RA. Accordingly, Ifnar1-/- mice experience increased joint swelling in the K/BxN serum transfer model of arthritis as compared to wild-type mice. Unexpectedly, targeting of Ikbke-/- enhances the level of arthritis in the Ifnar1-/- mice. Ifnar1-/- mice are neutrophilic and have expanded neutrophil-recruiting capacities. We propose that the mechanism by which IKK[Epsilon] enhances arthritis in the absence of interferon signaling is through the desensitization of neutrophils to apoptosis. IKK[Epsilon] deficiency prevents proper neutrophil clearance by prolonging neutrophil lifespan and delaying apoptosis. Therefore, arthritis in doubly deficient mice is enhanced by both the increased neutrophil recruiting capacities displayed by loss of interferon signaling and extended lifespans of these recruited neutrophils via loss of IKK[Epsilon]