Abstract
In gut epithelium, IL-22 transmits signals through STAT3 phosphorylation (pSTAT3) which provides intestinal immunity. Many components in the IL-22-pSTAT3 pathway have been identified as risk factors for inflammatory bowel disease (IBD) and some of them are considered as promising therapeutic targets. However, new perspectives are still needed to understand IL-22-pSTAT3 signaling for effective clinical interventions in IBD patients. Here, we revealed activating transcription factor 3 (ATF3), recently identified to be upregulated in patients with active IBD, as a crucial player in the epithelial IL-22-pSTAT3 signaling cascade. We found ATF3 is central to intestinal homeostasis and provides protection during colitis. Loss of ATF3 led to decreased crypt numbers, more shortened colon length, impaired ileal fucosylation at the steady state, and lethal disease activity during DSS-induced colitis which can be effectively ameliorated by rectal transplantation of wild-type colonic organoids. Epithelial stem cells and Paneth cells form a niche to orchestrate epithelial regeneration and host-microbe interactions, and IL-22-pSTAT3 signaling is a key guardian for this niche. We found ATF3 is critical for niche maintenance as ATF3 deficiency caused compromised stem cell growth and regeneration, as well as Paneth cell degeneration and loss of anti-microbial peptide (AMP)-producing granules, indicative of malfunction of Paneth/stem cell network. Mechanistically, we found IL-22 upregulates ATF3, which is required to relay IL-22 signaling leading to STAT3 phosphorylation and subsequent AMP induction. Intriguingly, ATF3 itself does not act on STAT3 directly, instead ATF3 regulates pSTAT3 by negatively targeting protein tyrosine phosphatases (PTPs) including SHP2 and PTP-Meg2. Furthermore, we identified ATF3 is also involved in IL-6-mediated STAT3 activation in T cells and loss of ATF3 leads to reduced capacity of Th17 cells to produce their signature cytokine IL-22 and IL-17A. Collectively, our results suggest that via IL-22-pSTAT3 signaling in the epithelium and IL-6-pSTAT3 signaling in Th17 cells, ATF3 mediates a cross-regulation in the barrier to maintain mucosal homeostasis and immunity.
Highlights
Inflammatory bowel disease (IBD) is a group of chronic relapsing inflammatory conditions characterized by impaired intestinal homeostasis and abnormal stress response [1]
Given the fact that increased activating transcription factor 3 (ATF3) level is associated with active IBD patients [21] and in order to better understand the function of ATF3 in the intestine, we first sought to determine the tissue distribution of ATF3 in more details
In light of a recent microarray analysis showing up-regulation of ATF3 in patients with active IBD [21], while lacking evidence supporting a role for ATF3 in intestinal homeostasis and IBD pathogenesis, we have performed in-depth analyses here, using primary intestinal organoids and animal models, to reveal how ATF3 is acting as a critical downstream regulator of the IL22 signaling cascade in intestinal epithelial cells
Summary
Inflammatory bowel disease (IBD) is a group of chronic relapsing inflammatory conditions characterized by impaired intestinal homeostasis and abnormal stress response [1]. It is well established that IL-22-STAT3 signaling controls epithelial stem cell regeneration [7], mucosal healing during colitis [8, 9], induction of anti-microbial, cytokine or chemokine genes, and production of mucins by IEC [10]. These IL-22-mediated biological processes are associated with host defense, intestinal inflammation, metabolic disorders (obesity, diabetes, or nephropathy), tumorigenesis, and even anti-TNF therapy for IBD [10,11,12,13,14,15,16]. A better understanding of IL-22 signaling network and its upstream or downstream transcriptional modulators will potentially improve the efficacy and safety of the current IBD drugs, or lead to identification of novel therapeutic targets for IBD treatment
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