A disintegrin and metalloproteinase 17 is required for IL-33 induced ILC2 expansion and cytokine production.

Abstract

Abstract Type 2 innate lymphoid cells (ILC2s) rapidly respond to the alarmins IL-25 and IL-33, resulting in the initiation of downstream Th2 responses, particularly in parasitic helminth infections. We show that A disintegrin and metalloprotease (ADAM) 17 is required for IL-33 mediated ILC2 activation. In vivo, mice that lack ADAM17 specifically on ILC2s (ADAM17ILC2−/−) exhibit decreased ILC2 expansion in response to intranasal IL-33 as well as Nippostrongylus brasiliensis (Nb) infection. In both of these models, the few ILC2s present in ADAM17ILC2−/− produce less IL-13 than WT ILC2s. Loss of ILC2 expansion in an Nb infection resulted in decreased numbers of IL-13 producing T cells as well as increased worm burden. However, ADAM17ILC2−/− mice have normal ILC2 numbers in a naïve state, suggesting this defect in ILC2 function is limited to cell activation. In vitro, IL-33 treatment of purified ILC2s in the presence of ADAM17 inhibitors show increased apoptosis and decreased IL-13 production compared to control (no ADAM17 inhibitor) ILC2s. The defect in cytokine production following ADAM17 inhibition was not observed in response to IL-25 stimulation, suggesting this defect is limited to IL-33 stimulation Mechanistically, ADAM17 inhibition in ILC2s specifically causes a defect in IL-33 mediated ERK activation, potentially explaining the reduced survival and IL-13 production following ADAM17 inhibition in these cells. Overall, these studies provide a targetable protease to target for the treatment of ILC2 mediated diseases.