Nrf2 suppresses allergic lung inflammation by attenuating the type2-innate lymphoid cell response

Abstract

Abstract The Keap1-Nrf2 system has an essential role in oxidative-stress responses by inducing a number of cytoprotective genes. Under stress, damaged epithelial cells release cytokines that activate Type 2 Innate lymphoid cells (ILC2s), which mediate the allergic immune response. Here we investigated the role of the Keap1-Nrf2 pathway in ILC2 homeostasis and allergic inflammation, using Nrf-2-knockout mice. ILC2s from Nrf2-deficient mice showed a transient, upregulated IL-33 response, and underwent hyper-proliferation in response to combined stimulation by IL-33 with IL-2, IL-7, or TSLP. This enhanced proliferation was correlated with an increased activation of downstream signals, including JAK1, Akt, and Erk1/2. In contrast, activating Nrf2 with a chemical inducer (CDDO-Im) decreased the viability of wild-type, but not of the Nrf2-deficient ILC2s. The reduced ILC2 viability resembled that exerted by the corticosteroid dexamethasone; however, unlike the latter, the Nrf2-dependent cell death was mediated by neither caspase 3-dependent apoptosis nor necroptosis. Using a mouse intratracheal IL-33-administration allergy model, we found that the activation of Nrf2 by CDDO-Im in vivo decreased the numbers of pulmonary ILC2s and eosinophils. These findings indicated that Nrf2 is an important regulator of the allergic response, by determining the survival and death of ILC2s, and suggest that Nrf2 activation is a potential therapeutic strategy for steroid-resistant allergy alleviation.