Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure
Milena Armacki, … , Alexander Kleger, Thomas Seufferlein
Milena Armacki, … , Alexander Kleger, Thomas Seufferlein
Published October 15, 2018
Citation Information: J Clin Invest. 2018;128(11):5056-5072. https://doi.org/10.1172/JCI97912.
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Research Article Gastroenterology Inflammation

Thirty-eight-negative kinase 1 mediates trauma-induced intestinal injury and multi-organ failure

Abstract

Dysregulated intestinal epithelial apoptosis initiates gut injury, alters the intestinal barrier, and can facilitate bacterial translocation leading to a systemic inflammatory response syndrome (SIRS) and/or multi-organ dysfunction syndrome (MODS). A variety of gastrointestinal disorders, including inflammatory bowel disease, have been linked to intestinal apoptosis. Similarly, intestinal hyperpermeability and gut failure occur in critically ill patients, putting the gut at the center of SIRS pathology. Regulation of apoptosis and immune-modulatory functions have been ascribed to Thirty-eight-negative kinase 1 (TNK1), whose activity is regulated merely by expression. We investigated the effect of TNK1 on intestinal integrity and its role in MODS. TNK1 expression induced crypt-specific apoptosis, leading to bacterial translocation, subsequent septic shock, and early death. Mechanistically, TNK1 expression in vivo resulted in STAT3 phosphorylation, nuclear translocation of p65, and release of IL-6 and TNF-α. A TNF-α neutralizing antibody partially blocked development of intestinal damage. Conversely, gut-specific deletion of TNK1 protected the intestinal mucosa from experimental colitis and prevented cytokine release in the gut. Finally, TNK1 was found to be deregulated in the gut in murine and porcine trauma models and human inflammatory bowel disease. Thus, TNK1 might be a target during MODS to prevent damage in several organs, notably the gut.

Authors

Milena Armacki, Anna Katharina Trugenberger, Ann K. Ellwanger, Tim Eiseler, Christiane Schwerdt, Lucas Bettac, Dominik Langgartner, Ninel Azoitei, Rebecca Halbgebauer, Rüdiger Groß, Tabea Barth, André Lechel, Benjamin M. Walter, Johann M. Kraus, Christoph Wiegreffe, Johannes Grimm, Annika Scheffold, Marlon R. Schneider, Kenneth Peuker, Sebastian Zeißig, Stefan Britsch, Stefan Rose-John, Sabine Vettorazzi, Eckhart Wolf, Andrea Tannapfel, Konrad Steinestel, Stefan O. Reber, Paul Walther, Hans A. Kestler, Peter Radermacher, Thomas F.E. Barth, Markus Huber-Lang, Alexander Kleger, Thomas Seufferlein

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Figure 8

TNK1-deficient mice (VilCreTNK1–/–) are less susceptible to DSS-induced colitis.

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TNK1-deficient mice (VilCreTNK1–/–) are less susceptible to DSS-induced ...
(A) Scheme of the knockout approach. (B and C) TNK1 knockout abolishes TNK1 expression, as shown in mini–gut organoids (A, bottom) and intestine from VilCreTnk1–/– mice (mRNA [B] and protein [C]). In response to DSS-induced colitis, TNK1fl/fl mice show increased TNK1 expression as compared with untreated TNK1fl/fl mice (n = 8–10 per group): (B) mRNA and (C) protein. (D) Representative images of H&E-stained colonic sections of TNK1fl/fl mice with colitis display increased wall thickness, distortion of the crypt architecture, formation of crypt abscess with the loss of goblet cells, and diffuse infiltration with mononuclear cells. In contrast, sections of VilCreTnk1–/– display less severe acute colonic pathology with focal leukocyte infiltration. (E and F) Corresponding graphs represent scoring and grading of inflammation-associated histological changes (E) and quantification of mucin-positive goblet cells (F) (n = 5–10 per group). Leukocyte infiltration was confirmed by CD45 staining (D, bottom) and (G) quantification of the stained area (n = 5–10 per group). (H) TNK1fl/fl mice with colitis show impaired intestinal barrier as indicated by E-cadherin and claudin-1 staining. (I and J) Consistently with the lower histological score, VilCreTnk1–/– mice show decreased levels of the proinflammatory cytokines IL6 and Tnfa in colonic tissue (n = 8–10 per group). Data are expressed as mean ± SEM. Differences were tested by parametric 2-tailed, unpaired Student’s t tests. ANOVA test was applied for multiple-comparison analysis. The mean of each column was compared with the mean of a control column by Dunnett’s multiple-comparisons test. (*P = 0.01–0.05; **P = 0.001–0.01; ***P = 0.0001–0.001; ****P < 0.0001.) Scale bars: 50 μm (C); 100 μm (D); 10 μm (IF images).