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
Objective:The trigger receptor expressed on myeloid cells-2(TREM2)pathway in myeloid cells is a key disease-inducing immune signaling hub that is essential for detecting tissue damage and limiting its pathological spr...Objective:The trigger receptor expressed on myeloid cells-2(TREM2)pathway in myeloid cells is a key disease-inducing immune signaling hub that is essential for detecting tissue damage and limiting its pathological spread.However,the role and potential mechanisms of TREM2 in wound repair remain unclear.The purpose of this study was to determine the role and mechanism of TREM2 in skin wound healing in mice.Methods:Immunofluorescence staining was used to determine the expression and cellular localization of TREM2 and test the effects of TREM2 knockout on angiogenesis,glycolysis,and lactylation in skin tissue.Western blotting was used to analyze the expression of the Akt/mTOR/HIF-1αsignaling pathway in the wounded skin tissues of wild-type(WT)and TREM2 knockout mice.A coimmunoprecipitation assay was used to determine whether HIF-1α,which mediates++angiogenesis,is modified by lactylation.Results:The number of TREM2 macrophages was increased,and TREM2 macrophages mediated angiogenesis after skin injury.TREM2 promoted glycolysis and lactylation in macrophages during wound healing.Mechanistically,TREM2 promoted macrophage glycolysis and angiogenesis in wounded skin tissues by activating the Akt/mTOR/HIF-1αsignaling pathway.HIF-1αcolocalized with Klac to mediate lactylation in macrophages,and lactate could stabilize the expression of the HIF-1αprotein through lactylation.Lactate treatment ameliorated the impaired angiogenesis and delayed wound healing in wounded skin in TREM2 knockout mice.Conclusion:TREM2^(+)macrophage-mediated glycolysis can promote angiogenesis and wound healing.Our findings provide an effective strategy and target for promoting skin wound healing.展开更多
Background:Alveolar macrophage pyroptosis exacerbates inflammatory lung diseases,and tanshinone IIA is known for its anti-inflammatory properties.Thus,understanding how tanshinone IIA affects alveolar macrophage pyrop...Background:Alveolar macrophage pyroptosis exacerbates inflammatory lung diseases,and tanshinone IIA is known for its anti-inflammatory properties.Thus,understanding how tanshinone IIA affects alveolar macrophage pyroptosis is essential.Methods:NR8383 cells were exposed to lipopolysaccharide(LPS)and adenosine triphosphate(ATP).We assessed cell viability,pyroptosis,and the expression of triggering receptors expressed on myeloid cells 2(TREM2),p-β-catenin,β-catenin,and pyroptosis-related factors.We also examined the interaction between tanshinone IIA and TREM2.Results:Co-stimulation with LPS and ATP significantly reduced NR8383 cell viability,increased pyroptosis,and upregulated pyroptosis-associated factors.Treatment with tanshinone IIA mitigated these effects.Tanshinone IIA was effectively bound to the TREM2 protein.Knockdown of TREM2 reduced its expression and the p-β-catenin andβ-catenin levels,thereby reversing the protective effects of tanshinone IIA.Conversely,overexpression of TREM2 enhanced NR8383 cell viability,reduced pyroptosis,and suppressed pyroptosis-related factors following LPS and ATP co-stimulation.Furthermore,the NOD-like receptor family pyrin domain containing 3(NLRP3)activation reversed the reduced pyroptosis induced byβ-catenin overexpression.β-catenin knockdown reversed the protective effects of TREM2 overexpression,and activation of NLRP3 exacerbated pyroptosis inβ-catenin knockdown cells.Conclusion:Tanshinone IIA inhibited NLRP3 activation and alleviated alveolar macrophage pyroptosis through the TREM2/β-catenin pathway.展开更多
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)。
基金supported by grants from the Science and Technology Fund Project of Wuhan(No.2023020201010183)National Natural Science Foundation of China(No.81803157).
文摘Objective:The trigger receptor expressed on myeloid cells-2(TREM2)pathway in myeloid cells is a key disease-inducing immune signaling hub that is essential for detecting tissue damage and limiting its pathological spread.However,the role and potential mechanisms of TREM2 in wound repair remain unclear.The purpose of this study was to determine the role and mechanism of TREM2 in skin wound healing in mice.Methods:Immunofluorescence staining was used to determine the expression and cellular localization of TREM2 and test the effects of TREM2 knockout on angiogenesis,glycolysis,and lactylation in skin tissue.Western blotting was used to analyze the expression of the Akt/mTOR/HIF-1αsignaling pathway in the wounded skin tissues of wild-type(WT)and TREM2 knockout mice.A coimmunoprecipitation assay was used to determine whether HIF-1α,which mediates++angiogenesis,is modified by lactylation.Results:The number of TREM2 macrophages was increased,and TREM2 macrophages mediated angiogenesis after skin injury.TREM2 promoted glycolysis and lactylation in macrophages during wound healing.Mechanistically,TREM2 promoted macrophage glycolysis and angiogenesis in wounded skin tissues by activating the Akt/mTOR/HIF-1αsignaling pathway.HIF-1αcolocalized with Klac to mediate lactylation in macrophages,and lactate could stabilize the expression of the HIF-1αprotein through lactylation.Lactate treatment ameliorated the impaired angiogenesis and delayed wound healing in wounded skin in TREM2 knockout mice.Conclusion:TREM2^(+)macrophage-mediated glycolysis can promote angiogenesis and wound healing.Our findings provide an effective strategy and target for promoting skin wound healing.
基金National Natural Science Foundation of China Youth Fund(Nos.82305214 and 82004306)Excellent Youth Project of Hunan Provindial Department of Eduation(No.22B0394)+2 种基金Halth Research Project of Hunan Provincial Health Commission(No.W20243178)Hunan Provincial Adninistration of Traditional Chinese Medicine General Guidance Project(No.E2022018)Hunan Natural Science Foundation Project(No.2023JJ40401).
文摘Background:Alveolar macrophage pyroptosis exacerbates inflammatory lung diseases,and tanshinone IIA is known for its anti-inflammatory properties.Thus,understanding how tanshinone IIA affects alveolar macrophage pyroptosis is essential.Methods:NR8383 cells were exposed to lipopolysaccharide(LPS)and adenosine triphosphate(ATP).We assessed cell viability,pyroptosis,and the expression of triggering receptors expressed on myeloid cells 2(TREM2),p-β-catenin,β-catenin,and pyroptosis-related factors.We also examined the interaction between tanshinone IIA and TREM2.Results:Co-stimulation with LPS and ATP significantly reduced NR8383 cell viability,increased pyroptosis,and upregulated pyroptosis-associated factors.Treatment with tanshinone IIA mitigated these effects.Tanshinone IIA was effectively bound to the TREM2 protein.Knockdown of TREM2 reduced its expression and the p-β-catenin andβ-catenin levels,thereby reversing the protective effects of tanshinone IIA.Conversely,overexpression of TREM2 enhanced NR8383 cell viability,reduced pyroptosis,and suppressed pyroptosis-related factors following LPS and ATP co-stimulation.Furthermore,the NOD-like receptor family pyrin domain containing 3(NLRP3)activation reversed the reduced pyroptosis induced byβ-catenin overexpression.β-catenin knockdown reversed the protective effects of TREM2 overexpression,and activation of NLRP3 exacerbated pyroptosis inβ-catenin knockdown cells.Conclusion:Tanshinone IIA inhibited NLRP3 activation and alleviated alveolar macrophage pyroptosis through the TREM2/β-catenin pathway.
