Background:Acute-on-chronic liver failure(ACLF)is a severe syndrome with high short-term mortality.Triggering receptor expressed on myeloid cells-2(TREM2)is highly expressed in the livers of patients with ACLF,but the...Background:Acute-on-chronic liver failure(ACLF)is a severe syndrome with high short-term mortality.Triggering receptor expressed on myeloid cells-2(TREM2)is highly expressed in the livers of patients with ACLF,but the role of its soluble form,soluble TREM2(sTREM2),in ACLF is not clear.Methods:We enrolled 96 consecutive patients receiving liver transplantation(LT),including 40 ACLF patients and 56 non-ACLF patients,and collected plasma at pre-LT and day 3,7 and 14 after LT.We also enrolled 22 healthy controls(HC).The plasma sTREM2 level was detected using the enzyme-linked immunosorbent assay.The expression of TREM2 in the livers was examined using quantitative polymerase chain reaction.Results:The pre-LT sTREM2 of the ACLF group was significantly higher than that of the non-ACLF group(13.4 ng/mL vs.2.6 ng/mL,P<0.001)and the HC group(13.4 ng/mL vs.0.57 ng/mL,P<0.001),but sTREM2 did not correlate with the grades of ACLF.The level of sTREM2 was positively correlated with the expression of TREM2 in the livers and had tight correlations with liver function and liver failure-related scores.To diagnose ACLF,sTREM2 showed an area under the receiver operating characteristic curve(AUC)of 0.863(P<0.001).When the cut-off value was 6.5 ng/mL,the sensitivity was 74.3%and the specificity was 93.0%.sTREM2 levels tested at day 7 and 14 after LT were associated with mortality[hazard ratio(HR):1.187 and 1.078,P<0.001 and P=0.043,respectively],and sTREM2 tested at day 3 after LT was a risk factor for early allograft dysfunction(EAD)[odds ratio(OR):1.060,P=0.023].Conclusions:sTREM2 was a good biomarker for liver injury.Pre-LT sTREM2 could be used to diagnose ACLF and persistently high levels of sTREM2 after LT predicted poor survival and incidence of EAD.展开更多
Triggering receptor expressed on myeloid cells 2(TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta(Aβ)clearance in Alzheimer’s disease(AD).Energy metabo...Triggering receptor expressed on myeloid cells 2(TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta(Aβ)clearance in Alzheimer’s disease(AD).Energy metabolic reprogramming(EMR)in microglia induced by TREM2 presents therapeutic targets for cognitive impairment in AD.Jiawei Xionggui Decoction(JWXG)has demonstrated effectiveness in enhancing energy supply,protecting microglia,and mitigating cognitive impairment in APP/PS1 mice.However,the mechanism by which JWXG enhances Aβphagocytosis through TREM2-mediated EMR in microglia remains unclear.This study investigates how JWXG facilitates microglial phagocytosis and alleviates cognitive deficits in AD through TREM2-mediated EMR.Microglial phagocytosis was evaluated through immunofluorescence staining in vitro and in vivo.The EMR level of microglia was assessed using high-performance liquid chromatography(HPLC)and enzyme-linked immunosorbent assay(ELISA)kits.The TREM2/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxia-inducible factor-1α(HIF-1α)signaling pathway was analyzed using Western blotting in BV_(2) cells.TREM2^(−/−)BV_(2) cells were utilized for reverse validation experiments.The Aβburden,neuropathological features,and cognitive ability in APP/PS1 mice were evaluated using ELISA kits,immunohistochemistry(IHC),and the Morris water maze(MWM)test.JWXG enhanced both the phagocytosis of EMR disorder-BV_(2) cells(EMRD-BV_(2))and increased EMR levels.Notably,these effects were significantly reversed in TREM2^(−/−)BV_(2) cells.JWXG elevated TREM2 expression,adenosine triphosphate(ATP)levels,and microglial phagocytosis in APP/PS1 mice.Additionally,JWXG reduced Aβ-burden,neuropathological lesions,and cognitive deficits in APP/PS1 mice.In conclusion,JWXG promoted TREM2-induced EMR and enhanced microglial phagocytosis,thereby reducing Aβdeposition,improving neuropathological lesions,and alleviating cognitive deficits.展开更多
基金supported by a grant from the National Natural Science Foundation of China(82300857)。
文摘Background:Acute-on-chronic liver failure(ACLF)is a severe syndrome with high short-term mortality.Triggering receptor expressed on myeloid cells-2(TREM2)is highly expressed in the livers of patients with ACLF,but the role of its soluble form,soluble TREM2(sTREM2),in ACLF is not clear.Methods:We enrolled 96 consecutive patients receiving liver transplantation(LT),including 40 ACLF patients and 56 non-ACLF patients,and collected plasma at pre-LT and day 3,7 and 14 after LT.We also enrolled 22 healthy controls(HC).The plasma sTREM2 level was detected using the enzyme-linked immunosorbent assay.The expression of TREM2 in the livers was examined using quantitative polymerase chain reaction.Results:The pre-LT sTREM2 of the ACLF group was significantly higher than that of the non-ACLF group(13.4 ng/mL vs.2.6 ng/mL,P<0.001)and the HC group(13.4 ng/mL vs.0.57 ng/mL,P<0.001),but sTREM2 did not correlate with the grades of ACLF.The level of sTREM2 was positively correlated with the expression of TREM2 in the livers and had tight correlations with liver function and liver failure-related scores.To diagnose ACLF,sTREM2 showed an area under the receiver operating characteristic curve(AUC)of 0.863(P<0.001).When the cut-off value was 6.5 ng/mL,the sensitivity was 74.3%and the specificity was 93.0%.sTREM2 levels tested at day 7 and 14 after LT were associated with mortality[hazard ratio(HR):1.187 and 1.078,P<0.001 and P=0.043,respectively],and sTREM2 tested at day 3 after LT was a risk factor for early allograft dysfunction(EAD)[odds ratio(OR):1.060,P=0.023].Conclusions:sTREM2 was a good biomarker for liver injury.Pre-LT sTREM2 could be used to diagnose ACLF and persistently high levels of sTREM2 after LT predicted poor survival and incidence of EAD.
基金supported by the National Natural Science Foundation of China(Nos.82074150 and 82274240)the Natural Science Foundation of Sichuan Province(No.2023NSFSC1779).
文摘Triggering receptor expressed on myeloid cells 2(TREM2)-mediated microglial phagocytosis is an energy-intensive process that plays a crucial role in amyloid beta(Aβ)clearance in Alzheimer’s disease(AD).Energy metabolic reprogramming(EMR)in microglia induced by TREM2 presents therapeutic targets for cognitive impairment in AD.Jiawei Xionggui Decoction(JWXG)has demonstrated effectiveness in enhancing energy supply,protecting microglia,and mitigating cognitive impairment in APP/PS1 mice.However,the mechanism by which JWXG enhances Aβphagocytosis through TREM2-mediated EMR in microglia remains unclear.This study investigates how JWXG facilitates microglial phagocytosis and alleviates cognitive deficits in AD through TREM2-mediated EMR.Microglial phagocytosis was evaluated through immunofluorescence staining in vitro and in vivo.The EMR level of microglia was assessed using high-performance liquid chromatography(HPLC)and enzyme-linked immunosorbent assay(ELISA)kits.The TREM2/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxia-inducible factor-1α(HIF-1α)signaling pathway was analyzed using Western blotting in BV_(2) cells.TREM2^(−/−)BV_(2) cells were utilized for reverse validation experiments.The Aβburden,neuropathological features,and cognitive ability in APP/PS1 mice were evaluated using ELISA kits,immunohistochemistry(IHC),and the Morris water maze(MWM)test.JWXG enhanced both the phagocytosis of EMR disorder-BV_(2) cells(EMRD-BV_(2))and increased EMR levels.Notably,these effects were significantly reversed in TREM2^(−/−)BV_(2) cells.JWXG elevated TREM2 expression,adenosine triphosphate(ATP)levels,and microglial phagocytosis in APP/PS1 mice.Additionally,JWXG reduced Aβ-burden,neuropathological lesions,and cognitive deficits in APP/PS1 mice.In conclusion,JWXG promoted TREM2-induced EMR and enhanced microglial phagocytosis,thereby reducing Aβdeposition,improving neuropathological lesions,and alleviating cognitive deficits.
基金supported by the National Natural Science Foundation of China (No. 81601228)Hubei Provincial Natural Science Foundation Innovation and Development Joint Fund Project of China (No. 2024AFD242)the Major Programs of Universities of Philosophy and Social Science (No. 23ZD165)。
