Role of Notch signaling in basophils in Type 2 inflammation

Abstract

Abstract Basophils are rare innate granulocytes, making up just 1% of circulating immune cells. Despite their rarity, basophils expand and contribute to the development of host-protective type 2 inflammation and worm expulsion following infection with Trichuris muris, a murine model of human whipworm. However, the pathways that regulate basophil expansion and function in this setting remain unclear. Previous work has shown that the Notch signaling pathway is important in lymphopoiesis and the function of T helper 2 cells, but little is known about its role in innate immune cells. Here, we have investigated the importance of the Notch signaling pathway in controlling the function of basophils during Type 2 inflammation. We show for the first time that basophils selectively upregulate Notch under Type 2 inflammatory conditions. Further, Notch is required for optimal cytokine production from basophils in response to such damage signals as IL-33. Using mice that selectively lack Notch signaling in basophils, we demonstrate that basophil expansion during T. muris infection depends on Notch signaling. Further, efficient clearance of T. muris also depends on effective Notch signaling in basophils. We are now actively investigating how other facets of basophil function are affected by inhibition of Notch signaling. These findings have wide reaching implications for our understanding of innate cell function in Type 2 immunity and for the potential development of therapeutics aimed at targeting Type 2 inflammation. Given that Notch inhibitors are on their way to the clinic, a clear understanding on their impact on Type 2 effector responses is essential. Our work suggests that these therapies could be re-purposed to control aberrant Type 2 immunity.