Abstract
Sepsis is caused by a dysregulated host inflammatory response to serious infections resulting in life-threatening organ dysfunction. The high morbidity and mortality make sepsis still a major clinical problem. Here, we investigated the roles of Brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BIG1) in the pathogenesis process of sepsis and the underlying mechanisms. We found myeloid cell-specific BIG1 knockout (BIG1 cKO) significantly reduced the mortality and organ damage in LPS-induced and CLP-induced polymicrobial sepsis mouse model. The serum concentration and mRNA expression of pro-inflammatory cytokines including TNF-α, IL-6, IL-1β, and IL-12 were obviously decreased in BIG1 cKO mice. In bone marrow-derived macrophages or THP-1 cells, BIG1 deficiency caused an inhibited ARF3 activation, which reduced PI(4,5)P2 synthesis and the recruitment of TIRAP to the plasma membrane through inhibiting the activation of PIP5K induced by LPS, and eventually resulted in the inhibitory activity of TLR4-MyD88 signaling pathway. These results reveal a crucial new role of BIG1 in regulating macrophage inflammation responses, and provide evidence for BIG1 as a potential promising therapeutic target in sepsis.
Highlights
Sepsis is considered to be a life-threatening organ dysfunction caused by a dysregulated host response to infection[1,2]
In order to explore the possible involvement of Brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BIG1) in infective inflammation, we firstly detected whether the expression of BIG1 in bone marrow-derived macrophages (BMDMs) was changed after LPS stimulation
We compared the levels of tumor necrosis factor (TNF)-α, IL-6, and IL-1β in WT and BIG1−/− Bone marrow-derived macrophages (BMDMs) stimulated with LPS for 12 or 24 h
Summary
Sepsis is considered to be a life-threatening organ dysfunction caused by a dysregulated host response to infection[1,2]. Despite significant advances in the early identification and treatment of sepsis have been achieved, the occurrence of sepsis-induced multiple organ failure and the resulting deaths are still a major clinical problem and clearly impose a substantial global burden[4,5]. Macrophages have comprehensive effects on immune homeostasis and inflammatory response, and play essential roles during the pathological process of sepsis. In the early stage of sepsis, macrophages are excessively activated through the binding of toll-like receptor (TLR) with pathogen-associated molecular patterns (PAMPs) of the invading pathogen, such as lipopolysaccharide (LPS) in gram-negative bacteria, resulting in the excessive secretion of massive amounts of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin1β (IL-1β), and interleukin-6 (IL-6)[9], which is considered as one of the leading causes for the high mortality in the early stage of sepsis[10,11]. Controlling excessive inflammatory response of macrophages in the early stage of sepsis can be of great benefits for sepsis-caused mortality[12]
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