Reactive Oxygen Species Regulate Innate But Not Adaptive Inflammation in ZAP70-Mutated SKG Arthritic Mice

Polysaccharides from Saccharomyces cerevisiae can induce arthritis, ileitis, and interstitial pneumonitis in BALB/c ZAP70 (W163C)-mutant (SKG) mice via T helper 17-cell–dependent pathways. However, little is known regarding the factors influencing disease severity. We investigated mannan-induced arthritis in SKG mice and how NADPH oxidase 2–derived reactive oxygen species (ROS) regulate disease. SKG mice were highly susceptible to both IL-17–mediated T-cell–driven arthritis and T-cell–independent acute psoriasis-like dermatitis. In vivo imaging revealed more ROS in joints of arthritic SKG mice compared to wild-type mice, which links ROS and joint inflammation. Still, ROS deficiency in SKG.Ncf1m1j/m1j mice greatly increased severity of arthritis and dermatitis, a difference that could not be attributed to increased T-cell activation, thymic selection, or antibody production. However, when ROS production was restored in CD68+ macrophages, inflammation reverted to baseline, demonstrating a regulatory role of macrophage-derived ROS in autoimmunity. Thus, arthritis in SKG mice is a useful model to study the role of ROS in innate-driven chronic inflammation independently of adaptive immunity.