hnRNP I regulates neonatal immune adaptation and prevents colitis and colorectal cancer

• Published in: PLoS genetics 2017-03, Vol.13 (3), p.e1006672-e1006672
• Main Authors: Jin, Zhigang, Liang, Feng, Yang, Jing, Mei, Wenyan
• Format: Article
• Language: English
• Subjects: Adaptation; Adaptive Immunity - genetics; Animals; Animals, Newborn; Antigens; Autoimmune diseases; Biology and Life Sciences; Blotting, Western; Care and treatment; Colitis; Colitis - genetics; Colitis - metabolism; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Cytokines; Epithelial cells; Epithelial Cells - metabolism; Epithelium; Female; Gastroenterology; Gene Expression; Health aspects; Heterogeneous-Nuclear Ribonucleoproteins - genetics; Heterogeneous-Nuclear Ribonucleoproteins - metabolism; Homeostasis; Immune response; Immune response regulation; Immunohistochemistry; Immunological tolerance; In Situ Hybridization, Fluorescence; Inflammatory bowel disease; Inflammatory diseases; Interleukin 1; Interleukin-1 Receptor-Associated Kinases - metabolism; Intestinal microflora; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestine; Invasiveness; IRAK protein; Kinases; Male; Medicine and Health Sciences; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Neonates; Newborn infants; NF-kappa B - metabolism; NF-κB protein; Polypyrimidine Tract-Binding Protein - genetics; Polypyrimidine Tract-Binding Protein - metabolism; Prevention; Proteins; Research and Analysis Methods; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; RNA-binding protein; Small intestine; Toll-like receptors; Uterus; Veterinary colleges; Veterinary medicine
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006672

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.