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Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion.

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Date
2018-06
Authors
Karhausen, Jörn
Bernstock, Joshua D
Johnson, Kory R
Sheng, Huaxin
Ma, Qing
Shen, Yuntian
Yang, Wei
Hallenbeck, John M
Paschen, Wulf
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Abstract
The intestinal epithelium constitutes a crucial defense to the potentially life-threatening effects of gut microbiota. However, due to a complex underlying vasculature, hypoperfusion and resultant tissue ischemia pose a particular risk to function and integrity of the epithelium. The small ubiquitin-like modifier (SUMO) conjugation pathway critically regulates adaptive responses to metabolic stress and is of particular significance in the gut, as inducible knockout of the SUMO-conjugating enzyme Ubc9 results in rapid intestinal epithelial disintegration. Here we analyzed the pattern of individual SUMO isoforms in intestinal epithelium and investigated their roles in intestinal ischemia/reperfusion (I/R) damage. Immunostaining revealed that epithelial SUMO2/3 expression was almost exclusively limited to crypt epithelial nuclei in unchallenged mice. However, intestinal I/R or overexpression of Ubc9 caused a remarkable enhancement of epithelial SUMO2/3 staining along the crypt-villus axis. Unexpectedly, a similar pattern was found in SUMO1 knockout mice. Ubc9 transgenic mice, but also SUMO1 knockout mice were protected from I/R injury as evidenced by better preserved barrier function and blunted inflammatory responses. PCR array analysis of microdissected villus-tip epithelia revealed a specific epithelial contribution to reduced inflammatory responses in Ubc9 transgenic mice, as key chemotactic signaling molecules such as IL17A were significantly downregulated. Together, our data indicate a critical role particularly of the SUMO2/3 isoforms in modulating responses to I/R and provide the first evidence that SUMO1 deletion activates a compensatory process that protects from ischemic damage.
Type
Journal article
Subject
Intestinal Mucosa
Animals
Mice, Inbred C57BL
Mice, Knockout
Mice
Reperfusion Injury
Ubiquitin-Conjugating Enzymes
Ubiquitins
Small Ubiquitin-Related Modifier Proteins
SUMO-1 Protein
Chemokines
Laser Capture Microdissection
Permalink
https://hdl.handle.net/10161/23251
Published Version (Please cite this version)
10.1038/s41374-018-0035-6
Publication Info
Karhausen, Jörn; Bernstock, Joshua D; Johnson, Kory R; Sheng, Huaxin; Ma, Qing; Shen, Yuntian; ... Paschen, Wulf (2018). Ubc9 overexpression and SUMO1 deficiency blunt inflammation after intestinal ischemia/reperfusion. Laboratory investigation; a journal of technical methods and pathology, 98(6). pp. 799-813. 10.1038/s41374-018-0035-6. Retrieved from https://hdl.handle.net/10161/23251.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Karhausen

Jorn Karhausen

Adjunct Associate Professor in the Department of Anesthesiology

Qing Ma

Assistant Professor in Anesthesiology
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.

Wulf Paschen

Professor in Anesthesiology
My research interests are understanding the mechanisms underlying induction of cell death induced by a severe form of cellular stress. I am particularly interested in the role of the endoplasmic reticulum in the pathological process induced by transient cerebral ischemia and culminating in neuronal cell death. This pathological process is associated with an irreversible suppression of protein synthese that limits the ability of cells to withstand ischemia-induced impairment of endoplasmic r
Sheng

Huaxin Sheng

Associate Professor in Anesthesiology
We have successfully developed various rodent models of brain and spinal cord injuries in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma, subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression injury. We also established cardiac arrest and hemorrhagic shock models for studying multiple organ dysfunction.  Our current studies focus on two projects. One is to examine the efficacy of catalytic antioxidant in treating cerebral is

Wei Yang

Associate Professor in Anesthesiology
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