RNA-binding protein RBM3 intrinsically suppresses lung innate lymphoid cell activation and inflammation partially through CysLT1R

Abstract

Innate lymphoid cells (ILC) promote lung inflammation in asthma through cytokine production. RNA-binding proteins (RBPs) are critical post-transcriptional regulators, although less is known about RBPs in ILC biology. Here, we demonstrate that RNA-binding motif 3 (RBM3) is highly expressed in lung ILCs and is further induced by alarmins TSLP and IL-33. Rbm3−/− and Rbm3−/−Rag2−/− mice exposed to asthma-associated Alternaria allergen develop enhanced eosinophilic lung inflammation and ILC activation. IL-33 stimulation studies in vivo and in vitro show that RBM3 suppressed lung ILC responses. Further, Rbm3−/− ILCs from bone marrow chimeric mice display increased ILC cytokine production suggesting an ILC-intrinsic suppressive function of RBM3. RNA-sequencing of Rbm3−/− lung ILCs demonstrates increased expression of type 2/17 cytokines and cysteinyl leukotriene 1 receptor (CysLT1R). Finally, Rbm3−/−Cyslt1r−/− mice show dependence on CysLT1R for accumulation of ST2+IL-17+ ILCs. Thus, RBM3 intrinsically regulates lung ILCs during allergen-induced type 2 inflammation that is partially dependent on CysLT1R.

Circulating NK cells establish tissue residency upon acute infection of skin and mediate accelerated effector responses to secondary infection

“…Although it is currently unclear when and where trNK cell commitment occurs and whether the cellular states in spleen and skin are actually connected at this day 8 pi “snapshot” of gene expression, this analysis highlighted several interesting genes regulated along this trajectory, including the following: Satb1 , a chromatin organizer with a function in maintaining the naive state of CD8 + T cells before activation, 38 the lysine demethylase 6b ( Kdm6b ) involved in effector differentiation of CD8 + T cells and NK cells, 39 and the RNA-binding protein 3 ( Rbm3 ) that has been suggested to increase β-catenin signaling, and thereby activity of Tcf/Lef transcription factors, and to restrain activation of ILC2s. 40 Other interesting genes include Stat3 , which regulates responsiveness to cytokines, Ifngr1 , involved in ILC1 differentiation, 41 and Smad7 , which can antagonize TGF-β signaling and thereby may inhibit signals from concomitantly upregulated Tgfb1 . 42 …”

Alternative 3′UTR expression induced by T cell activation is regulated in a temporal and signal dependent manner

“…Interestingly, our data do suggest a previously unknown mechanism for APA regulation in T cell via induced expression of RBM3 early upon T cell activation. RBM3 is a stress-induced protein that has been implicated in cytokine expression in innate lymphoid cells 39 , and has neural protective activity 40 . We show here that expression of RBM3 mRNA and protein are markedly enhanced early after T cell activation and this correlates with 3′UTR shortening of genes that have an RBM3 binding motif immediately overlapping the distal PAS site.…”

Regulation of mRNA stability contributes to the function of innate lymphoid cells in various diseases

“…First, even though multiple cytokines (e.g., IL-12, IL-18) have been shown to have important regulatory roles on ILC1s function, mRNA stability-related RBPs in ILC1s have not been identified, which merits further investigation. Second, several RBPs have been shown to have important roles in the regulation of ILC2s function, including regnase-1, TTP, and RNA-binding protein 3 (RBM3) ( 124 ). Specifically, regnase-1 and TTP have broad roles in mRNA stability in ILCs and other cell subsets.…”

“…However, RBM3 has a potentially specific role in ILC2s because studies have shown that RBM3 deficiency has no effects on the numbers of NK cells, T cells, or B cells in mice. Hence, RBM3 might be an ILC2s-specific RBP in immune cells ( 124 ). Third, a few studies have reported that circRNAs can regulate downstream mRNAs stability in ILC3s indirectly ( 125 – 127 ).…”