2. Academic Validation
  3. A lncRNA from an inflammatory bowel disease risk locus maintains intestinal host-commensal homeostasis

A lncRNA from an inflammatory bowel disease risk locus maintains intestinal host-commensal homeostasis

  • Cell Res. 2023 Apr 13. doi: 10.1038/s41422-023-00790-7.
Hongdi Ma # 1 2,  Taidou Hu # 1 2,  Wanyin Tao 1 2,  Jiyu Tong 3,  Zili Han 1 2,  Dietmar Herndler-Brandstetter 3,  Zheng Wei 3,  Ruize Liu 4,  Tingyue Zhou 1 2,  Qiuyuan Liu 5,  Xuemei Xu 1,  Kaiguang Zhang 1,  Rongbin Zhou 2,  Judy H Cho 6,  Hua-Bing Li 7,  Hailiang Huang 8,  Richard A Flavell 9 10,  Shu Zhu 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Digestive Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 2 Institute of Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  • 3 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
  • 4 Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 5 The Key Laboratory of Digestive Diseases of Anhui Province, Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
  • 6 Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
  • 7 Shanghai Institute of Immunology, Department of Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China. [email protected].
  • 8 Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
  • 9 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. [email protected].
  • 10 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA. [email protected].
  • 11 Department of Digestive Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. [email protected].
  • 12 Institute of Immunology, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. [email protected].
  • 13 School of Data Science, University of Science and Technology of China, Hefei, Anhui, China. [email protected].
  • 14 Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui, China. [email protected].
  • # Contributed equally.
PMID: 37055591 DOI: 10.1038/s41422-023-00790-7
Abstract

Inflammatory bowel diseases (IBD) are known to have complex, genetically influenced etiologies, involving dysfunctional interactions between the intestinal immune system and the microbiome. Here, we characterized how the RNA transcript from an IBD-associated long non-coding RNA locus ("CARINH-Colitis Associated IRF1 antisense Regulator of Intestinal Homeostasis") protects against IBD. We show that CARINH and its neighboring gene coding for the transcription factor IRF1 together form a feedforward loop in host myeloid cells. The loop activation is sustained by microbial factors, and functions to maintain the intestinal host-commensal homeostasis via the induction of the anti-inflammatory factor IL-18BP and anti-microbial factors called guanylate-binding proteins (GBPs). Extending these mechanistic insights back to humans, we demonstrate that the function of the CARINH/IRF1 loop is conserved between mice and humans. Genetically, the T allele of rs2188962, the most probable causal variant of IBD within the CARINH locus from the human genetics study, impairs the inducible expression of the CARINH/IRF1 loop and thus increases genetic predisposition to IBD. Our study thus illustrates how an IBD-associated lncRNA maintains intestinal homeostasis and protects the host against colitis.

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