Synergistic effect of the TLR5 agonist CBLB502 and its downstream effector IL-22 against liver injury.

Melin, Nicolas; Sánchez-Taltavull, Daniel; Fahrner, René; Keogh, Adrian; Dosch, Michel; Büchi, Isabel; Zimmer, Yitzhak; Medová, Michaela; Beldi, Guido; Aebersold, Daniel M.; Candinas, Daniel; Stroka, Deborah (2021). Synergistic effect of the TLR5 agonist CBLB502 and its downstream effector IL-22 against liver injury. Cell death & disease, 12(4), p. 366. Nature Publishing Group 10.1038/s41419-021-03654-3

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The toll-like receptor 5 (TLR5) agonist, CBLB502/Entolimod, is a peptide derived from bacterial flagellin and has been shown to protect against radiation-induced tissue damage in animal models. Here we investigated the protective mechanism of CBLB502 in the liver using models of ischemia-reperfusion injury and concanavalin A (ConA) induced immuno-hepatitis. We report that pretreatment of mice with CBLB502 provoked a concomitant activation of NF-κB and STAT3 signaling in the liver and reduced hepatic damage in both models. To understand the underlying mechanism, we screened for cytokines in the serum of CBLB502 treated animals and detected high levels of IL-22. There was no transcriptional upregulation of IL-22 in the liver, rather it was found in extrahepatic tissues, mainly the colon, mesenteric lymph nodes (MLN), and spleen. RNA-seq analysis on isolated hepatocytes demonstrated that the concomitant activation of NF-κB signaling by CBLB502 and STAT3 signaling by IL-22 produced a synergistic cytoprotective transcriptional signature. In IL-22 knockout mice, the loss of IL-22 resulted in a decrease of hepatic STAT3 activation, a reduction in the cytoprotective signature, and a loss of hepatoprotection following ischemia-reperfusion-induced liver injury. Taken together, these findings suggest that CBLB502 protects the liver by increasing hepatocyte resistance to acute liver injury through the cooperation of TLR5-NF-κB and IL-22-STAT3 signaling pathways.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine

UniBE Contributor:

Melin, Nicolas; Sánchez Taltavull, Daniel; Keogh, Adrian; Dosch, Michel Ernest Jean-Pierre; Büchi, Isabel; Zimmer, Yitzhak; Medova, Michaela; Beldi, Guido; Aebersold, Daniel; Candinas, Daniel and Keogh-Stroka, Deborah M.

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2041-4889

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Beatrice Scheidegger

Date Deposited:

11 May 2021 16:00

Last Modified:

16 May 2021 03:04

Publisher DOI:

10.1038/s41419-021-03654-3

PubMed ID:

33824326

BORIS DOI:

10.48350/155735

URI:

https://boris.unibe.ch/id/eprint/155735

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