c-Rel Is Required for IL-33-Dependent Activation of ILC2s

Abstract

Group 2 innate lymphoid cells (ILC2s) are emerging as important cellular regulators of homeostatic and disease-associated immune processes. The cytokine interleukin-33 (IL-33) promotes ILC2-dependent inflammation and immunity, with IL-33 having been shown to activate NF-κB in a wide variety of cell types. However, it is currently unclear which NF-κB members play an important role in IL-33-dependent ILC2 biology. Here, we identify the NF-κB family member c-Rel as a critical component of the IL-33-dependent activation of ILC2s. Although c-Rel is dispensable for ILC2 development, it is critical for ILC2 function in the lung, with c-Rel-deficient (c-Rel–/–) mice present a significantly reduced response to papain- and IL-33-induced lung inflammation. We also show that the absence of c-Rel reduces the IL-33-dependent expansion of ILC2 precursors and lower levels of IL-5 and IL-13 cytokine production by mature ILC2s in the lung. Together, these results identify the IL-33-c-Rel axis as a central control point of ILC2 activation and function.

The alarmin IL-33 exacerbates pulmonary inflammation and immune dysfunction in SARS-CoV-2 infection

“…Of note, IL-33 may also promote Th2 differentiation and ILC2 activation via NF-κB activation, which leads to pulmonary fibrosis. 33 , 34 , 35 , 36 , 37 , 38 More research is needed to illustrate the exact role(s) of IL-33 during the recovery stages of COVID-19.…”

SLAM-family receptors promote resolution of ILC2-mediated inflammation

“…Given the pivotal role of the NF-κB pathway in cytokine production by ILC2, as elucidated in previous studies 4, 45,46 , along with the demonstrated suppressive capability of SHIP-1 on the NF-κB pathway [47][48][49] , our objective was to investigate whether SLAMF3 and SLAMF5 could potentially inhibit the NF-κB signal in ILC2s. We observed a reduction in expression of IκB, an inhibitor of NF-κB whose expression showed an inverse correlation with NF-κB activity 50 , in MLN ILC2s lacking SLAMF3 and SLAMF5 (Fig.…”