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 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.

Mesenchymal stem cells paracrine proteins from three‐dimensional dynamic culture system promoted wound healing in third‐degree burn models

“…), and even cause excessive inflammatory response (such as CD47, CCL2, etc.). 34,35 Although there are only 465 protein species in the 3D group, among which these proteins can specifically promote the mediation of cell attachment and migration (such as LAMA1, POSTN, TLN1, etc. ), promote cell proliferation (such as PRKDC, ASCC3, MYH10, PDK1, etc.…”

“…2.9 | Release behavior study of PEG thermogel loaded with MSC-PP PEG thermogel loaded with MSC-PP was prepared by direct mixing PEG micelle solution with a specific concentration (30,35, and 40 mg/ mL). After solidification, the mixed micelle solution was taking a water bath at 37 C to form MSC-PP-released hydrogels.…”

Rapid dexamethasone treatment inhibits LPS-induced cytokine storm in mice

“…To inhibit individual cytokine in LPS-treated mice, Adalimumab solution for injection (anti-TNF-α, 10mg/kg dosage, Hisun Biopharmaceutical, Taizhou, China) [11], InVivoMAb anti-mouse IL-6R (8mg/kg dosage, Bio X Cell, New Hampshire, USA) [12], and Raleukin (IL-1R antagonist, 10 or 20mg/kg dosage, MedChemExpress, New Jersey, USA) [13] were used.…”

Macrophage: Hidden Criminal in Therapy Resistance

“…In support of this finding, infliximab-non-responding IBD patients ( n = 38) have a higher enrichment of several monocyte/macrophage subsets than infliximab-responding patients ( n = 28) [ 76 ]. Similar to anti-TNF-α mAb, the IL-6 receptor antibody tocilizumab inhibited the pro-inflammatory activation and infiltration of macrophages in mice [ 77 ]. In RA patients, the reduction in macrophage numbers was only observed in responders ( n = 37) but not in nonresponders ( n = 42) after tocilizumab treatment [ 78 ].…”