Blockade of mIL‐6R alleviated lipopolysaccharide‐induced systemic inflammatory response syndrome by suppressing NF‐κB‐mediated Ccl2 expression and inflammasome activation. Issue 2 (6th May 2022)

• Record Type: Journal Article
• Authors: Dai, Ji‐Min; Zhang, Xue‐Qin; Zhang, Jia‐Jia; Yang, Wei‐Jie; Yang, Xiang‐Min; Bian, Huijie; Chen, Zhi‐Nan
• Is Part Of: MedComm. Volume 3:Issue 2(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-05-06
• Subjects: Ccl2 -- mIL‐6R -- monoclonal antibody -- NF‐κB -- pyroptosis -- SIRS; 610
• DOI: 10.1002/mco2.132
• Languages: English
• ISSNs: 2688-2663

Abstract

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. Abstract : SIRS is characterized by dysregulated cytokine release and inflammatory responses. IL‐6R mAbs like Tocilizumab displays therapeutic effects in cytokine release storm and inflammatory diseases but 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 IL‐6R (mIL‐6R) monoclonal antibody named h‐mIL‐6R mAb. We found that the h‐mIL‐6R mAb and Tocilizumab alleviated LPS‐induced SIRS in the transgenic mice. Besides, the h‐mIL‐6R mAb could also inhibit Ccl2 expression and NLRP3‐mediated pyroptosis by suppressing the NF‐κB signaling pathway. This study indicated that mIL‐6R mAbs suppressed NF‐κB/Ccl2 signaling and inflammasome activation in LPS‐induced inflammatory responses and SIRS.