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 1

Expression of TNK1 causes animal distress, systemic inflammation, and rapid lethality.

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Expression of TNK1 causes animal distress, systemic inflammation, and ra...
(A) By an inducible cassette exchange (ICE) approach (60), Myc-tagged Tnk1 was targeted to a specific conditionally regulated locus by Cre-lox recombination. (B) Behavior analysis shows that expression of TNK1 impairs locomotion of the animals (n = 6 per group). (C and D) TNK1-expressing mice show signs of cachexia, as demonstrated by decreased food intake (C) and body weight (D) (n = 12 per group, t = 24 hours). (E) Mice exhibit a drop in body temperature upon TNK1 expression (n = 5 per group, t = 24 hours). (F) TNK-expressing mice exhibit hypoglycemia (left) and hypercortisolism (right) (n = 4 per group). (G) Differential blood count suggests systemic bacterial inflammation (n = 8–10 per group, t = 24 hours), as designated by an increase in the total number of white blood cells (WBC), granulocytes, and monocytes and a decrease of lymphocytes. (H) TNK1-expressing mice show a significant decrease in red blood cell (RBC) number, declined hematocrit (HCT), and hemoglobin (HGB). (I–K) TNK1-expressing mice also exhibit a dysregulation of coagulation, as indicated by diminished platelets (n = 9 per group) (I) and rotational thromboelastometry analysis (n = 3–4 per group) (J and K) (t = 24 hours). Prolonged EXTEM (J) and FIBTEM (K) clotting time (CT) and reduced α angle specify abnormal clot formation. A prolonged EXTEM clot formation time (CFT) and reduced EXTEM maximum clot firmness (MCF) indicate abnormal clot formation in TNK1-expressing mice (J, right 2 graphs). (L) Kaplan-Meier analysis shows decreased survival upon TNK1 expression (n = 12). MS, median survival. Data are expressed as mean ± SEM. Differences were tested by parametric 2-tailed, unpaired Student’s t tests (*P = 0.01–0.05; **P = 0.001–0.01; ***P = 0.0001–0.001; ****P < 0.0001).