2. Academic Validation
  3. Microbial signals, MyD88, and lymphotoxin drive TNF-independent intestinal epithelial tissue damage

Microbial signals, MyD88, and lymphotoxin drive TNF-independent intestinal epithelial tissue damage

  • J Clin Invest. 2022 Mar 1;132(5):e154993. doi: 10.1172/JCI154993.
Iulia Rusu 1,  Elvira Mennillo 1,  Jared L Bain 1,  Zhongmei Li 1 2,  Xiaofei Sun 1,  Kimberly M Ly 3,  Yenny Y Rosli 1,  Mohammad Naser 4,  Zunqiu Wang 1,  Rommel Advincula 1,  Philip Achacoso 1,  Ling Shao 5,  Bahram Razani 6,  Ophir D Klein 7,  Alexander Marson 1 2 3 8 9 10 11,  Jessie A Turnbaugh 3,  Peter J Turnbaugh 3,  Barbara A Malynn 1,  Averil Ma 1,  Michael G Kattah 1
Affiliations

Affiliations

  • 1 Department of Medicine, UCSF, San Francisco, California, USA.
  • 2 Gladstone Institutes, San Francisco, California, USA.
  • 3 Department of Microbiology and Immunology and.
  • 4 Biological Imaging Development CoLab, UCSF, San Francisco, California, USA.
  • 5 Department of Medicine, University of Southern California, Los Angeles, California, USA.
  • 6 Department of Dermatology.
  • 7 Departments of Orofacial Sciences and Pediatrics, Program in Craniofacial Biology, and.
  • 8 Institute for Human Genetics, UCSF, San Francisco, California, USA.
  • 9 Innovative Genomics Institute, University of California, Berkeley, California, USA.
  • 10 Parker Institute for Cancer Immunotherapy, San Francisco, California, USA.
  • 11 Chan Zuckerberg Biohub, San Francisco, California, USA.
PMID: 35077396 DOI: 10.1172/JCI154993
Abstract

Anti-TNF Antibodies are effective for treating patients with inflammatory bowel disease (IBD), but many patients fail to respond to anti-TNF therapy, highlighting the importance of TNF-independent disease. We previously demonstrated that acute deletion of 2 IBD susceptibility genes, A20 (Tnfaip3) and Abin-1 (Tnip1), in intestinal epithelial cells (IECs) sensitized mice to both TNF-dependent and TNF-independent death. Here we show that TNF-independent IEC death after A20 and Abin-1 deletion was rescued by germ-free derivation or deletion of MyD88, while deletion of Trif provided only partial protection. Combined deletion of RIPK3 and Casp8, which inhibits both apoptotic and necroptotic death, completely protected against death after acute deletion of A20 and Abin-1 in IECs. A20- and Abin-1-deficient IECs were sensitized to TNF-independent, TNFR1-mediated death in response to lymphotoxin α (LTα) homotrimers. Blockade of LTα in vivo reduced weight loss and improved survival when combined with partial deletion of MyD88. Biopsies of inflamed colon mucosa from patients with IBD exhibited increased LTA and IL1B expression, including a subset of patients with active colitis on anti-TNF therapy. These data show that microbial signals, MyD88, and LTα all contribute to TNF-independent intestinal injury.

Keywords

Apoptosis survival pathways; Gastroenterology; Immunology; Inflammatory bowel disease; Mouse models.

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