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

Abstract

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.

Keywords: NADPH oxidase; chronic granulomatous disease; innate lymphoid cells; reactive oxygen species; serum-induced arthritis.