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Microbial signals, MyD88, and lymphotoxin drive TNF-independent intestinal epithelial tissue damage
Iulia Rusu, … , Averil Ma, Michael G. Kattah
Iulia Rusu, … , Averil Ma, Michael G. Kattah
Published January 25, 2022
Citation Information: J Clin Invest. 2022;132(5):e154993. https://doi.org/10.1172/JCI154993.
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Research Article Gastroenterology Immunology Article has an altmetric score of 13

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

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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.

Authors

Iulia Rusu, Elvira Mennillo, Jared L. Bain, Zhongmei Li, Xiaofei Sun, Kimberly M. Ly, Yenny Y. Rosli, Mohammad Naser, Zunqiu Wang, Rommel Advincula, Philip Achacoso, Ling Shao, Bahram Razani, Ophir D. Klein, Alexander Marson, Jessie A. Turnbaugh, Peter J. Turnbaugh, Barbara A. Malynn, Averil Ma, Michael G. Kattah

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Figure 7

Intestinal Lta and Il1b are increased in A20/Abin-1T-ΔIEC Tnf–/– mice and anti-LTα improves survival in A20/Abin-1T-ΔIEC Tnf–/– MyD88+/+ and A20/Abin-1T-ΔIEC Tnf–/– MyD88+/– mice.

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Intestinal Lta and Il1b are increased in A20/Abin-1T-ΔIEC Tnf–/– mice an...
(A) Representative chromogenic RNA-ISH images of Lta and (B) quantitation of Lta area. (C and D) qPCR for (C) Lta and (D) Il1b in small intestine and colon 40 hours after tamoxifen treatment in mice with the indicated genotype; each data point represents 1 mouse (mean ± SEM). (E and G) Weight curve and (F and H) Kaplan-Meier survival curves of the indicated genotypes of tamoxifen-treated mice treated with anti-LTα or isotype control antibody. For panel B, statistical significance was assessed using 2-way ANOVA. For panels C and D, significance was assessed using 1-way ANOVA with Dunnett’s multiple-comparison test relative to A20/Abin-1T-ΔIEC Tnf–/– mice. For panels E and G, significance was assessed by 2-way ANOVA with Bonferroni’s multiple-comparison test. For panels F and H, significance was assessed by log-rank Mantel-Cox test. Only significant differences are shown. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Scale bars: 50 μm. Data represent at least 2 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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