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

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 Fe Barth; Markus Huber-Lang; Alexander Kleger; Thomas Seufferlein

doi:10.1172/JCI97912

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

J Clin Invest. 2018 Nov 1;128(11):5056-5072. doi: 10.1172/JCI97912. Epub 2018 Oct 15.

Authors

Milena Armacki¹, Anna Katharina Trugenberger¹, Ann K Ellwanger¹, Tim Eiseler¹, Christiane Schwerdt², Lucas Bettac¹, Dominik Langgartner³, Ninel Azoitei¹, Rebecca Halbgebauer⁴, Rüdiger Groß¹, Tabea Barth¹, André Lechel¹, Benjamin M Walter¹, Johann M Kraus⁵, Christoph Wiegreffe⁶, Johannes Grimm⁷, Annika Scheffold⁸, Marlon R Schneider⁹, Kenneth Peuker¹⁰, Sebastian Zeißig¹⁰, Stefan Britsch⁶, Stefan Rose-John¹¹, Sabine Vettorazzi¹², Eckhart Wolf⁹, Andrea Tannapfel¹³, Konrad Steinestel¹⁴, Stefan O Reber³, Paul Walther¹⁵, Hans A Kestler⁵, Peter Radermacher¹⁶, Thomas Fe Barth⁷, Markus Huber-Lang⁴, Alexander Kleger¹, Thomas Seufferlein¹

Affiliations

¹ Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
² Waldkrankenhaus "Rudolph Elle" Eisenberg, Lehrstuhl für Orthopädie Uniklinik Jena, Jena, Germany.
³ Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy, and.
⁴ Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany.
⁵ Institute of Medical Systems Biology and.
⁶ Institute of Molecular and Cellular Anatomy, Ulm University, Ulm, Germany.
⁷ Institute of Pathology and.
⁸ Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
⁹ Gene Center, LMU Munich, Munich, Germany.
¹⁰ Center for Regenerative Therapies Dresden, TU Dresden, Dresden, Germany.
¹¹ Institute of Biochemistry, CA University Kiel, Kiel, Germany.
¹² Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Germany.
¹³ Institute of Pathology, Ruhr University Bochum, Bochum, Germany.
¹⁴ Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Ulm, Germany.
¹⁵ Central Facility for Electron Microscopy, University of Ulm, Ulm, Germany.
¹⁶ Institute of Anesthesiological Pathophysiology and Process Engineering, Ulm University, Ulm, Germany.

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.

Keywords: Apoptosis; Gastroenterology; Inflammation; Inflammatory bowel disease; Tight junctions.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Female
Fetal Proteins / genetics
Fetal Proteins / metabolism*
Inflammatory Bowel Diseases / enzymology*
Inflammatory Bowel Diseases / etiology
Inflammatory Bowel Diseases / genetics
Inflammatory Bowel Diseases / pathology
Interleukin-6 / genetics
Interleukin-6 / metabolism
Intestines / enzymology*
Intestines / pathology
Mice
Multiple Organ Failure / enzymology*
Multiple Organ Failure / etiology
Multiple Organ Failure / genetics
Multiple Organ Failure / pathology
Multiple Trauma / complications
Multiple Trauma / enzymology*
Multiple Trauma / genetics
Multiple Trauma / pathology
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism*
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism
Swine
Systemic Inflammatory Response Syndrome / enzymology*
Systemic Inflammatory Response Syndrome / etiology
Systemic Inflammatory Response Syndrome / pathology
Transcription Factor RelA / genetics
Transcription Factor RelA / metabolism
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / metabolism

Substances

Fetal Proteins
IL6 protein, human
Interleukin-6
RELA protein, human
Rela protein, mouse
STAT3 Transcription Factor
STAT3 protein, human
Stat3 protein, mouse
Transcription Factor RelA
Tumor Necrosis Factor-alpha
interleukin-6, mouse
Protein-Tyrosine Kinases
Kos1 protein, mouse
TNK1 protein, human

Grants and funding

This work was supported by CRC1149 Project A6, DFG AZ.96/1-3, DFG STE 2467/1-1, DFG KL. 2544/ 1-2, the Forschungskern SyStaR, BIU (Böhringer Ingelheim), the NDIMED-Verbund PancChip, the Else-Kröner-Fresenius- Stiftung-2011_A200, the Fritz-Thyssen Foundation-2015-00363.