Blockade of mIL‐6R alleviated lipopolysaccharide‐induced systemic inflammatory response syndrome by suppressing NF‐κB‐mediated Ccl2 expression and inflammasome activation
Abstract Systemic inflammatory response syndrome (SIRS) is characterized by dysregulated cytokine release, immune responses and is associated with organ dysfunction. IL‐6R blockade indicates promising therapeutic effects in cytokine release storm but still remains unknown in SIRS. To address the iss...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-06-01
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| Series: | MedComm |
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| Online Access: | https://doi.org/10.1002/mco2.132 |
| _version_ | 1811250334933188608 |
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| author | Ji‐Min Dai Xue‐Qin Zhang Jia‐Jia Zhang Wei‐Jie Yang Xiang‐Min Yang Huijie Bian Zhi‐Nan Chen |
| author_facet | Ji‐Min Dai Xue‐Qin Zhang Jia‐Jia Zhang Wei‐Jie Yang Xiang‐Min Yang Huijie Bian Zhi‐Nan Chen |
| author_sort | Ji‐Min Dai |
| collection | DOAJ |
| description | Abstract Systemic inflammatory response syndrome (SIRS) is characterized by dysregulated cytokine release, immune responses and is associated with organ dysfunction. IL‐6R blockade indicates promising therapeutic effects in cytokine release storm but still remains unknown in SIRS. To address the issue, we generated the human il‐6r knock‐in mice and a defined epitope murine anti‐human membrane‐bound IL‐6R (mIL‐6R) mAb named h‐mIL‐6R mAb. We found that the h‐mIL‐6R and the commercial IL‐6R mAb Tocilizumab significantly improved the survival rate, reduced the levels of TNF‐α, IL‐6, IL‐1β, IFN‐γ, transaminases and blood urea nitrogen of LPS‐induced SIRS mice. Besides, the h‐mIL‐6R mAb could also dramatically reduce the levels of inflammatory cytokines in LPS‐treated THP‐1 cells in vitro. RNA‐seq analysis indicated that the h‐mIL‐6R mAb could regulate LPS‐induced activation of NF‐κB/Ccl2 and NOD‐like receptor signaling pathways. Furthermore, we found that the h‐mIL‐6R mAb could forwardly inhibit Ccl2 expression and NLRP3‐mediated pyroptosis by suppressing NF‐κB in combination with the NF‐κB inhibitor. Collectively, mIL‐6R mAbs suppressed NF‐κB/Ccl2 signaling and inflammasome activation. IL‐6R mAbs are potential alternative therapeutics for suppressing excessive cytokine release, over‐activated inflammatory responses and alleviating organ injuries in SIRS. |
| first_indexed | 2024-04-12T16:03:05Z |
| format | Article |
| id | doaj.art-154e0c7013a14c5390f5645635429187 |
| institution | Directory Open Access Journal |
| issn | 2688-2663 |
| language | English |
| last_indexed | 2024-04-12T16:03:05Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj.art-154e0c7013a14c5390f56456354291872022-12-22T03:26:09ZengWileyMedComm2688-26632022-06-0132n/an/a10.1002/mco2.132Blockade of mIL‐6R alleviated lipopolysaccharide‐induced systemic inflammatory response syndrome by suppressing NF‐κB‐mediated Ccl2 expression and inflammasome activationJi‐Min Dai0Xue‐Qin Zhang1Jia‐Jia Zhang2Wei‐Jie Yang3Xiang‐Min Yang4Huijie Bian5Zhi‐Nan Chen6National Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. ChinaNational Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. ChinaNational Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. ChinaNational Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. ChinaNational Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. ChinaNational Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. ChinaNational Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. ChinaAbstract Systemic inflammatory response syndrome (SIRS) is characterized by dysregulated cytokine release, immune responses and is associated with organ dysfunction. IL‐6R blockade indicates promising therapeutic effects in cytokine release storm but still remains unknown in SIRS. To address the issue, we generated the human il‐6r knock‐in mice and a defined epitope murine anti‐human membrane‐bound IL‐6R (mIL‐6R) mAb named h‐mIL‐6R mAb. We found that the h‐mIL‐6R and the commercial IL‐6R mAb Tocilizumab significantly improved the survival rate, reduced the levels of TNF‐α, IL‐6, IL‐1β, IFN‐γ, transaminases and blood urea nitrogen of LPS‐induced SIRS mice. Besides, the h‐mIL‐6R mAb could also dramatically reduce the levels of inflammatory cytokines in LPS‐treated THP‐1 cells in vitro. RNA‐seq analysis indicated that the h‐mIL‐6R mAb could regulate LPS‐induced activation of NF‐κB/Ccl2 and NOD‐like receptor signaling pathways. Furthermore, we found that the h‐mIL‐6R mAb could forwardly inhibit Ccl2 expression and NLRP3‐mediated pyroptosis by suppressing NF‐κB in combination with the NF‐κB inhibitor. Collectively, mIL‐6R mAbs suppressed NF‐κB/Ccl2 signaling and inflammasome activation. IL‐6R mAbs are potential alternative therapeutics for suppressing excessive cytokine release, over‐activated inflammatory responses and alleviating organ injuries in SIRS.https://doi.org/10.1002/mco2.132Ccl2mIL‐6Rmonoclonal antibodyNF‐κBpyroptosisSIRS |
| spellingShingle | Ji‐Min Dai Xue‐Qin Zhang Jia‐Jia Zhang Wei‐Jie Yang Xiang‐Min Yang Huijie Bian Zhi‐Nan Chen Blockade of mIL‐6R alleviated lipopolysaccharide‐induced systemic inflammatory response syndrome by suppressing NF‐κB‐mediated Ccl2 expression and inflammasome activation MedComm Ccl2 mIL‐6R monoclonal antibody NF‐κB pyroptosis SIRS |
| title | Blockade of mIL‐6R alleviated lipopolysaccharide‐induced systemic inflammatory response syndrome by suppressing NF‐κB‐mediated Ccl2 expression and inflammasome activation |
| title_full | Blockade of mIL‐6R alleviated lipopolysaccharide‐induced systemic inflammatory response syndrome by suppressing NF‐κB‐mediated Ccl2 expression and inflammasome activation |
| title_fullStr | Blockade of mIL‐6R alleviated lipopolysaccharide‐induced systemic inflammatory response syndrome by suppressing NF‐κB‐mediated Ccl2 expression and inflammasome activation |
| title_full_unstemmed | Blockade of mIL‐6R alleviated lipopolysaccharide‐induced systemic inflammatory response syndrome by suppressing NF‐κB‐mediated Ccl2 expression and inflammasome activation |
| title_short | Blockade of mIL‐6R alleviated lipopolysaccharide‐induced systemic inflammatory response syndrome by suppressing NF‐κB‐mediated Ccl2 expression and inflammasome activation |
| title_sort | blockade of mil 6r alleviated lipopolysaccharide induced systemic inflammatory response syndrome by suppressing nf κb mediated ccl2 expression and inflammasome activation |
| topic | Ccl2 mIL‐6R monoclonal antibody NF‐κB pyroptosis SIRS |
| url | https://doi.org/10.1002/mco2.132 |
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