Bone marrow stromal cells attenuate LPS-induced mouse acute liver injury via the prostaglandin E 2-dependent repression of the NLRP3 inflammasome in Kupffer cells.
The nucleotide-binding and oligomerization domain-like receptor 3 (NLRP3) inflammasome participates in the pathogenesis of acute liver injury during sepsis. Bone marrow mesenchymal stem cells (BMSCs) attenuate sepsis through prostaglandin E 2 (PGE2) by increasing the interleukin-10 (IL-10) production of macrophages; moreover, NLRP3 inflammasome assembly is effectively regulated by IL-10 during infection. Whether BMSCs have an effect on the activation of the NLRP3 inflammasome and its underlying mechanism is unclear. Administering of BMSCs to mice or KCs after LPS stimulating have improved liver function and reduced activation of NLRP3 inflammasome in KCs. The beneficial effect of BMSCs was enhanced by over-expression of PGE2 and eliminated by silence of PGE2. Additionally, The IL-10 levels in the serum and supernatant were increased by given BMSCs and further increase by PGE2 over-expressed BMSCs, but decreased markedly by PGE2 silenced BMSCs. Furthermore, extracellular signal-regulated kinase 1 (ERK1) inhibitor reduced IL-10 production in KCs and blocked the inhibitory effect of PGE2 on the activation of the NLRP3 inflammasome. Our data reveal a novel mechanism of BMSC-mediated suppression of the activation of KCs through the secretion of PGE2 by BMSCs, which promotes KCs to secrete IL-10, leading to the inhibition of the NLRP3 inflammasome in KCs.
Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Chun-Mu
CM
Miao
Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Xiao-Wei
XW
Jiang
Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Kun
K
He
Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Pei-Zhi
PZ
Li
Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Zuo-Jin
ZJ
Liu
Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Ding
D
Cao
Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Zhi-Bing
ZB
Ou
Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Jian-Ping
JP
Gong
Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: liuchangan120@163.com.
Chang-An
CA
Liu
Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: 124139153@QQ.com.
Yao
Y
Cheng
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers; D001706:Biopsy; D020170:Caspase 1 / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D058847:Inflammasomes / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000276:immunology*; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*
D015415:Biomarkers; D016207:Cytokines; D058847:Inflammasomes; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020170:Caspase 1; D015232:Dinoprostone
Acute liver injury; BMSCs; Kupffer cells; NLRP3; PGE2