Abstract
The intestinal epithelium plays a critical role in host-microbe homeostasis by sensing gut microbes and subsequently initiating proper immune responses. During the neonatal stage, the intestinal epithelium is under immune repression, allowing the transition for newborns from a relatively sterile intra-uterine environment to one that is rich in foreign antigens. The mechanism underlying such immune repression remains largely unclear, but involves downregulation of IRAK1 (interleukin-1 receptor-associated kinase), an essential component of toll-like receptor-mediated NF-κB signaling. We report here that heterogeneous nuclear ribonucleoprotein I (hnRNPI), an RNA binding protein, is essential for regulating neonatal immune adaptation. We generated a mouse model in which hnRNPI is ablated specifically in the intestinal epithelial cells, and characterized intestinal defects in the knockout mice. We found that loss of hnRNPI function in mouse intestinal epithelial cells results in early onset of spontaneous colitis followed by development of invasive colorectal cancer. Strikingly, the epithelium-specific hnRNPI knockout neonates contain aberrantly high IRAK1 protein levels in the colons and fail to develop immune tolerance to environmental microbes. Our results demonstrate that hnRNPI plays a critical role in establishing neonatal immune adaptation and preventing colitis and colorectal cancer.
Highlights
Increasing evidence indicates that proper host-microbe interaction in the gastrointestinal tract is critical for the balance of immune tolerance and active immune responses [1,2]
Dysregulated host responses to gut microbiota are the major cause of autoimmune diseases, inflammatory disorders and cancers
Junction complexes located between the intestinal epithelial cells (IECs) control the paracellular permeability of the intestinal epithelium, which is critical to prevent the invasion of pathogens and other luminal contents across the epithelial layer [9,10]
Summary
Increasing evidence indicates that proper host-microbe interaction in the gastrointestinal tract is critical for the balance of immune tolerance and active immune responses [1,2]. The intestinal epithelium, which lines the gastrointestinal tract, plays a fundamental role in controlling the host-microbe interaction [7]. In addition to acting as a physical barrier, IECs play an active role in immune defense by expressing a variety of molecules that recognize and subsequently kill pathogens, and initiating the innate and adaptive immune responses. A key event in transmitting signals from TLRs to NF-κB signaling is IRAK1-induced degradation of IκB, the cytosolic inhibitors of NF-κB signaling This releases NF-κB subunits from a cytoplasmic inhibitory complex, which allows them to translocate into the nucleus to induce transcription of pro-inflammatory genes. Understanding mechanisms by which TLR -mediated NF-κB signaling is precisely controlled in the IECs is critical for elucidating the etiology of gastrointestinal inflammatory disorders and its associated cancers
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