IGF2BP3 modulates type 2 immunity in severe asthma: A novel regulator of IL-4/IL-13 signalling

Background: There is extensive mechanistic research into T2 (IL-4, IL-13 and IL-5)-driven inflammation underlying severe asthma (SA) pathogenesis, focused on transcriptional changes and cytokine effects. However, mRNA and protein have little correlation because of microRNAs and RNA binding proteins (RBPs). Little is known about RBPs in SA and regulation of T2 signalling. Methods: We employed subcellular fractionation and RNA-seq (Frac-seq) to compare total (transcriptional) and polyribosome-bound (translation) mRNAs in bronchial epithelium. Knockdown of Insulin like Growth Factor-II mRNA binding protein III (IGF2BP3) was done to investigate its role in IL-4/IL-13-dependent signalling. mRNA and protein analyses were done by qPCR and western blotting, respectively. RNA immunoprecipitation was performed to determine the binding of mRNAs to IGF2BP3. Results: We found IGF2BP3 binds the mRNAs encoding IL4R and IL13RA1, the receptor subunits of IL-4 and IL-13. IGF2BP3 depletion increased IL-4Rα and IL-13Rα1 protein expression without affecting their mRNA levels, resulting in enhanced IL-13-dependent STAT6 phosphorylation and activation. Moreover, IGF2BP3 reduction led to elevated expression of IL-4 and IL-13-dependen CCL26 and CCL11 mRNAs. Frac-seq showed that IGF2BP3 depletion leads to genome-wide post-transcriptional regulation of IL-13-driven gene expression. IGF2BP3 expression is increased in airway epithelial cells and PBMCs is SA patients in our cohort and public datasets. Conclusions: IGF2BP3 is a novel regulator of IL-13 signalling in bronchial epithelium, placing RBPs as cytokine signalling modulators. IGF2BP3 upregulation in SA may be a new inhibitor to attenuate T2-driven pathology.