Increased ILC3s associated with higher levels of IL‐1β aggravates inflammatory arthritis in mice lacking phagocytic NADPH oxidase

The role of redox regulation in immune‐mediated arthritis has been previously described. However, the relationship between innate immune cells, including innate lymphoid cells (ILCs) and phagocyte‐derived ROS, in this process remains unclear. Here, we characterize ILCs and measure the IL‐1 family cytokines along with other cytokines relevant to ILC functions and development in serum‐induced arthritic joints in wild type and phagocytic NADPH oxidase (NOX2)‐deficient Ncf1−/− mice. We found more severe serum‐induced joint inflammation and increased NCR+ ILC3s in inflamed joints of Ncf1−/− mice. Furthermore, in vitro stimulation with IL‐1β on Tbet+ ILC1s from joints facilitated their differentiation into ROR‐γt+ ILC3s. Moreover, treatment with IL‐1 antagonists effectively lowered the proportions of NCR+ ILC3s and IL‐17A producing ILC3s in Ncf1−/− arthritic mice and ameliorated the joint inflammation. These results suggest that NOX2 is an essential regulator of ILC transdifferentiation and may mediate this process in a redox‐dependent manner through IL‐1β production in the inflammatory joint. Our findings shed important light on the role of ILCs in the initiation and progression in tissue inflammation and delineate a novel innate immune cell‐mediated pathogenic mechanism through which redox regulation may determine the direction of immune responses in joints. Innate lymphoid cells (ILCs) and cytokines were investigated in mice with different ROS production levels to reveal the immunopathogenesis of arthritis. The differentiation to NCR+ ILC3s induced by IL‐1β in joints with lower ROS may aggravate arthritis. This study highlights the redox‐IL1β axis as a target for arthritis treatment.