Synergistic effect of the TLR5 agonist CBLB502 and its downstream effector IL-22 against liver injury
Abstract 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-re...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-04-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-03654-3 |
| _version_ | 1818849778445844480 |
|---|---|
| author | Nicolas Melin Daniel Sánchez-Taltavull René Fahrner Adrian Keogh Michel Dosch Isabel Büchi Yitzhak Zimmer Michaela Medová Guido Beldi Daniel M. Aebersold Daniel Candinas Deborah Stroka |
| author_facet | Nicolas Melin Daniel Sánchez-Taltavull René Fahrner Adrian Keogh Michel Dosch Isabel Büchi Yitzhak Zimmer Michaela Medová Guido Beldi Daniel M. Aebersold Daniel Candinas Deborah Stroka |
| author_sort | Nicolas Melin |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-19T06:38:39Z |
| format | Article |
| id | doaj.art-9fb567e82f4d416b850bee9442bbda8c |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-19T06:38:39Z |
| publishDate | 2021-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-9fb567e82f4d416b850bee9442bbda8c2022-12-21T20:32:10ZengNature Publishing GroupCell Death and Disease2041-48892021-04-0112411210.1038/s41419-021-03654-3Synergistic effect of the TLR5 agonist CBLB502 and its downstream effector IL-22 against liver injuryNicolas Melin0Daniel Sánchez-Taltavull1René Fahrner2Adrian Keogh3Michel Dosch4Isabel Büchi5Yitzhak Zimmer6Michaela Medová7Guido Beldi8Daniel M. Aebersold9Daniel Candinas10Deborah Stroka11Department for BioMedical Research, Inselspital, Bern University Hospital, University of BernDepartment for BioMedical Research, Inselspital, Bern University Hospital, University of BernDepartment for BioMedical Research, Inselspital, Bern University Hospital, University of BernDepartment for BioMedical Research, Inselspital, Bern University Hospital, University of BernDepartment for BioMedical Research, Inselspital, Bern University Hospital, University of BernDepartment for BioMedical Research, Inselspital, Bern University Hospital, University of BernDepartment for BioMedical Research, Inselspital, Bern University Hospital, University of BernDepartment for BioMedical Research, Inselspital, Bern University Hospital, University of BernDepartment for BioMedical Research, Inselspital, Bern University Hospital, University of BernDepartment for BioMedical Research, Inselspital, Bern University Hospital, University of BernDepartment for BioMedical Research, Inselspital, Bern University Hospital, University of BernDepartment for BioMedical Research, Inselspital, Bern University Hospital, University of BernAbstract 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.https://doi.org/10.1038/s41419-021-03654-3 |
| spellingShingle | Nicolas Melin Daniel Sánchez-Taltavull René Fahrner Adrian Keogh Michel Dosch Isabel Büchi Yitzhak Zimmer Michaela Medová Guido Beldi Daniel M. Aebersold Daniel Candinas Deborah Stroka Synergistic effect of the TLR5 agonist CBLB502 and its downstream effector IL-22 against liver injury Cell Death and Disease |
| title | Synergistic effect of the TLR5 agonist CBLB502 and its downstream effector IL-22 against liver injury |
| title_full | Synergistic effect of the TLR5 agonist CBLB502 and its downstream effector IL-22 against liver injury |
| title_fullStr | Synergistic effect of the TLR5 agonist CBLB502 and its downstream effector IL-22 against liver injury |
| title_full_unstemmed | Synergistic effect of the TLR5 agonist CBLB502 and its downstream effector IL-22 against liver injury |
| title_short | Synergistic effect of the TLR5 agonist CBLB502 and its downstream effector IL-22 against liver injury |
| title_sort | synergistic effect of the tlr5 agonist cblb502 and its downstream effector il 22 against liver injury |
| url | https://doi.org/10.1038/s41419-021-03654-3 |
| work_keys_str_mv | AT nicolasmelin synergisticeffectofthetlr5agonistcblb502anditsdownstreameffectoril22againstliverinjury AT danielsancheztaltavull synergisticeffectofthetlr5agonistcblb502anditsdownstreameffectoril22againstliverinjury AT renefahrner synergisticeffectofthetlr5agonistcblb502anditsdownstreameffectoril22againstliverinjury AT adriankeogh synergisticeffectofthetlr5agonistcblb502anditsdownstreameffectoril22againstliverinjury AT micheldosch synergisticeffectofthetlr5agonistcblb502anditsdownstreameffectoril22againstliverinjury AT isabelbuchi synergisticeffectofthetlr5agonistcblb502anditsdownstreameffectoril22againstliverinjury AT yitzhakzimmer synergisticeffectofthetlr5agonistcblb502anditsdownstreameffectoril22againstliverinjury AT michaelamedova synergisticeffectofthetlr5agonistcblb502anditsdownstreameffectoril22againstliverinjury AT guidobeldi synergisticeffectofthetlr5agonistcblb502anditsdownstreameffectoril22againstliverinjury AT danielmaebersold synergisticeffectofthetlr5agonistcblb502anditsdownstreameffectoril22againstliverinjury AT danielcandinas synergisticeffectofthetlr5agonistcblb502anditsdownstreameffectoril22againstliverinjury AT deborahstroka synergisticeffectofthetlr5agonistcblb502anditsdownstreameffectoril22againstliverinjury |