传染病学传染病学 (24).pdf
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1、1Scientific RepoRts|6:33206|DOI:10.1038/ CD11clowCD45RBhigh dendritic cells derived from endotoxin-tolerant mice attenuate experimental acute liver failureSai-Nan Zhang1,*,Nai-Bin Yang1,*,Shun-Lan Ni1,*,Jin-Zhong Dong2,Chun-Wei Shi3,Shan-Shan Li1,Sheng-Guo Zhang1,Xin-Yue Tang1&Ming-Qin Lu1Endotoxin
2、tolerance(ET)is suggested to attenuate the severity of acute liver failure(ALF)in mice,possibly through both innate and adaptive immunity.However,the involvement of regulatory dendritic cells(DCregs)in ET has not been fully elucidated.In this study,their effect on ALF in mice was investigated.Spleni
3、c DCregs from ET-exposed mice(ET-DCregs)showed lower expression levels of CD40,CD80,and MHC-II markers and stronger inhibition of allogenic T cells and regulation of IL-10 and IL-12 secretion than splenic DCregs from normal mice(nDCregs).Moreover,the mRNA and protein levels of TNF-and P65 in splenic
4、 ET-DCregs were significantly lower than those in the splenic nDCregs.The survival rate was significantly increased and liver injury was mitigated in mice with ALF treated with splenic ET-DCregs.In addition,A20 expression was decreased in the liver of ALF mice,but elevated after infusion of splenic
5、nDCregs and ET-DCregs,and a much higher elevation was observed after infusing the latter cells.The functionality of splenic DCregs was altered after ET exposure,contributing to protection of the livers against D-GalN/LPS-induced ALF.Acute liver failure(ALF)is a life-threatening syndrome primarily ca
6、used by severe liver injury.Although the etiologies of ALF are diverse and the pathogenesis is still yet to be fully elucidated,disruption of the immune response has been reported upon ALF.Several animal models of ALF have been generated that can recapture the clinical phenotype and course of ALF1.F
7、or example,ALF can be induced by infusion of lipopolysaccharide(LPS)/D-galactosamine(D-GalN).In addition,we and others have demonstrated that pre-treatment of animals with a small amount of LPS attenuates the severity of D-GalN/LPS induced ALF(endotoxin tolerance,ET),and the mechanism responsible fo
8、r this protection is related to immune modulation of LPS through TLR4 signaling2.Although it is well known that innate immune cells like monocytes/macrophages,when exposed to a small amount of endotoxin,become endotoxin tolerant,the impact of exposure on other immune cells such as den-dritic cells(D
9、Cs)in the setting of ET remains unclear.DCs were first identified from the skin and named by Dr.Langerhans in 1868 because of their distinct morphological features with dendrites.Later studies revealed that DCs are one of the most important antigen-presenting cells(APCs)3,4.DCs circulate in peripher
10、al blood and reside in lymphoid tissues.The DCs in peripheral blood account for less than 1%of all peripheral blood mono-nuclear cells,but they are essential for bridging the innate and adaptive immune systems.DCs function to launch and coordinate appropriate immune responses to pathogens and to pri
11、me memory of immune cells so that the host will be under protection upon future infections4.As an early step of initiating an adaptive immune response to pathogens,DCs uptake,process,and present antigens to T cells57.The antigen presenting function of DCs is closely related to the expression of mark
12、er proteins on cellular surface including major histocompatibility com-plex class II(MHC-II)and costimulatory molecules CD80 and CD86.1Department of Infection Diseases,The First Affiliated Hospital of Wenzhou Medical University,Wenzhou Key Laboratory of Hepatology,Hepatology Institute of Wenzhou Med
13、ical University,Wenzhou 325000,Zhejiang,P.R.China.2Department of Intensive Care Unit,The First Hospital of Ningbo,Ningbo 315010,Zhejiang,P.R.China.3Department of Infection Diseases,The First Hospital of Xiaoshan,Hangzhou 311200,Zhejiang,P.R.China.*These authors contributed equally to this work.Corre
14、spondence and requests for materials should be addressed to M.-Q.L.(email:)Received:26 January 2016Accepted:22 August 2016Published:14 September 2016OPEN RepoRts|6:33206|DOI:10.1038/srep33206DCs can be classified into different subsets in line with their functions and/or developmental stages.The spl
15、enic DC class contains heterogeneous subsets of DCs with a spectrum of functions and morphologies8.One subset of DCs is regulatory DCs(DCregs),which modulate immune cells and contribute to the host immune tolerance by maintaining immune response at steady state.CD11ClowCD45RBhigh DCs,a subtype of DC
16、regs with low expression of CD11c and high expression of CD45RB,can respond to an inflammatory stimulus9.Recent studies also suggested that splenic DCregs inhibit inflammation by generating anergic T cells and regulatory T cells(Tregs),as well as deleting peripheral T cells under lethal conditions o
17、f endotoxemia and bacterial peritonitis10.Therefore,in the current study,we examined the effect of splenic DCs derived from LPS-pretreated mice on D-GalN/LPSinduced acute liver failure and explored the possible mechanisms underlying ET.Material and MethodsEthics statement.This research project inclu
18、ding survival analysis was approved by the Institute Animal Care and Use committee at Wenzhou Medical University(Approval Number:wydw2012-0053).Animal experiment.Male BALB/c mice aged 68 weeks were purchased from the Shanghai Laboratory Animal Center(Shanghai,China).All mice were caged in specific p
19、athogen-free rooms in the Experimental Animal Laboratory of Wenzhou Medical University(Wenzhou,Zhejiang,China)under standard laboratory con-ditions(laminar-flow,temperature-controlled by 21 2 C,humidity-regulated at 4070%,12-h light/dark cycle),fed with a standard chow diet and free water and treate
20、d in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.Experimental design.D-GalN(Sigma-Aldrich,St.Louis,MO,USA)and LPS(Sigma-Aldrich)were dis-solved in sterile 0.9%sodium chloride(NaCl).Mice were randomly divided into four groups:control group
21、(n=15),ALF group(n=20),nDCregs group(n=20),and ET-DCregs group(n=20).To establish the exper-imental model of ALF,all mice in the ALF,nDCregs,and ET-DCregs groups were intraperitoneally injected with 500 L of sterile 0.9%NaCl containing 20 mg D-GalN and 10 g/kg LPS.In control group,mice were intra-pe
22、ritoneally injected with 500 L of sterile 0.9%saline.After 30 minutes of D-GalN/LPS injection,nDCregs (106/mouse,200 l,i.p.)were infused into mice in the nDCregs group and ET-DCregs(106/mouse,200 l,i.p.)were administered into mice in the ET-DCregs group.As a control,mice in the ALF group were inject
23、ed with 200 l of sterile 0.9%saline.Three mice were sacrificed with chloral hydrate at time points of 2,6,12,24,and 48 hours after D-GalN/LPS injection.Both serum and liver samples were collected and stored at 80 C for fur-ther analysis.A portion of each liver specimen was fixed in 10%neutral formal
24、in for histopathological analysis.In a separate experiment,the 7-day mortality in another 40 mice consisting of control(n=10),ALF(n=10),nDCregs(n=10),and ET-DCregs(n=10)groups were monitored once every 6 hours after D-GalN/LPS injec-tion without euthanasia before the experimental endpoint.The aim of
25、 the 7-day survival analysis was to investi-gate the possible improvement by transferring splenic CD11clowCD45RBhigh DCs derived from endotoxin-tolerant mice in the survival rate of ALF mice.The observation for death after intraperitoneal injection of D-GalN/LPS with or without subsequent administra
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