Various cellular stress conditions trigger mitochondrial DNA(mtDNA)release from mitochondria into the cytosol.The released mtDNA is sensed by the cGAS-MITA/STING pathway,resulting in the induced expression of type I i...Various cellular stress conditions trigger mitochondrial DNA(mtDNA)release from mitochondria into the cytosol.The released mtDNA is sensed by the cGAS-MITA/STING pathway,resulting in the induced expression of type I interferon and other effector genes.These processes contribute to the innate immune response to viral infection and other stress factors.The deregulation of these processes causes autoimmune diseases,inflammatory metabolic disorders and cancer.Therefore,the cGAS-MITA/STING pathway is a potential target for intervention in infectious,inflammatory and autoimmune diseases as well as cancer.In this review,we focus on the mechanisms underlying the mtDNA-triggered activation of the cGAS-MITA/STING pathway,the effects of the pathway under various physiological and pathological conditions,and advances in the development of drugs that target cGAS and MITA/STING.展开更多
Upon viral infection, cytoplasmic pattern recognition receptors detect viral nucleic acids and activate the adaptor protein VISA/MAVS- or MITA/STING-mediated innate antiviral response. Whether and how the innate antiv...Upon viral infection, cytoplasmic pattern recognition receptors detect viral nucleic acids and activate the adaptor protein VISA/MAVS- or MITA/STING-mediated innate antiviral response. Whether and how the innate antiviral response is regulated by neuronal endocrine functions is unclear. Here, we show that viral infection reduced the serum levels of the β-adrenergic hormones epinephrine and norepinephrine as well as the cellular levels of their receptors ADRB1 and ADRB2. We further show that an increase in epinephrine/norepinephrine level inhibited the innate antiviral response in an ADRB1-/2-dependent manner. Mechanistically, epinephrine/norepinephrine stimulation activated the downstream kinase PKA, which catalyzed the phosphorylation of MITA at S241, S243 and T263, inhibiting MITA activation and suppressing the innate immune response to DNA virus. In addition, phosphorylation of VISA at T54 by PKA antagonized the innate immune response to RNA virus. These findings reveal the regulatory mechanisms of innate antiviral responses by epinephrine/norepinephrine and provide a possible explanation for increased host susceptibility to viral infection in stressful and anxiety-promoting situations.展开更多
Mitochondrial stress (mitostress) triggered by viral infection or mitochondrial dysfunction causes the release of mitochondrial DNA (mtDNA) into the cytosol and activates the cGAS-mediated innate immune response. The ...Mitochondrial stress (mitostress) triggered by viral infection or mitochondrial dysfunction causes the release of mitochondrial DNA (mtDNA) into the cytosol and activates the cGAS-mediated innate immune response. The regulation of mtDNA release upon mitostress remains uncharacterized. Here, we identified mitochondria-associated vaccinia virus-related kinase 2 (VRK2) as a key regulator of this process. VRK2 deficiency inhibited the induction of antiviral genes and caused earlier and higher mortality in mice after viral infection. Upon viral infection, VRK2 associated with voltage-dependent anion channel 1 (VDAC1) and promoted VDAC1 oligomerization and mtDNA release, leading to the cGAS-mediated innate immune response. VRK2 was also required for mtDNA release and cGAS-mediated innate immunity triggered by nonviral factors that cause Ca^(2+) overload but was not required for the cytosolic nucleic acid-triggered innate immune response. Thus, VRK2 plays a crucial role in the mtDNA-triggered innate immune response and may be a potential therapeutic target for infectious and autoimmune diseases associated with mtDNA release.展开更多
Interleukin-3(IL-3)is a hematopoietic growth factor and critical regulator of inflammatory response such as sepsis.IL-3 binds to IL-3 receptorα(IL-3Rα),which is then associated with IL-3Rβto initiate signaling.How ...Interleukin-3(IL-3)is a hematopoietic growth factor and critical regulator of inflammatory response such as sepsis.IL-3 binds to IL-3 receptorα(IL-3Rα),which is then associated with IL-3Rβto initiate signaling.How IL-3-triggered physiological and pathological effects are regulated at the receptor level is unclear.Here,we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates IL-3-triggered signaling.MARCH3 is associated with IL-3Rα,mediates its K48-linked polyubiquitination at K377 and promotes its proteasomal degradation.MARCH3-deficiency promotes IL-3-triggered transcription of downstream effector genes and IL-3-induced expansion of myeloid cells.In the cecal ligation and puncture(CLP)model of sepsis,MARCH3-deficiency aggravates IL-3-ampified expression of inflammatory cytokines,organ damage and inflammatory death.Our findings suggest that regulation of IL-3Rαby MARCH3 plays an important role in IL-3-triggered physiological functions and inflammatory diseases.展开更多
The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-mediator of interferon response factor 3 acti-vation/stimulator of interferon genes(MITA/STING)axis has emerged as a major pathway,which senses...The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-mediator of interferon response factor 3 acti-vation/stimulator of interferon genes(MITA/STING)axis has emerged as a major pathway,which senses microbial or mislocated cellular DNA in the cytosol to trigger innate immune responses.cGAS senses cytosolic DNA without a preference of self-or nonself-DNA.How the cGAS-MITA/STING axis is inactivated upon nuclear envelope breakdown(NEBD)at mitotic entry in vertebrate cells to avoid self-DNA sensing remains unclear until very recently.In this review,we summarize the recent advances on how cGAS responds to chromosomes upon NEBD and the mechanisms involved in the inactivation of the cGAS-MITA/STING pathways in mitosis.展开更多
Estrogen receptorα(ERα)is an important driver and therapeutic target in∼70%of breast cancers.How ERαdrives breast carcinogenesis is not fully understood.In this study,we show that ERαis a negative regulator of ty...Estrogen receptorα(ERα)is an important driver and therapeutic target in∼70%of breast cancers.How ERαdrives breast carcinogenesis is not fully understood.In this study,we show that ERαis a negative regulator of type I interferon(IFN)response.Activation of ERαby its natural ligand estradiol inhibits IFN-β-induced transcription of downstream IFN-stimulated genes(ISGs),whereas ERαdeficiency or the stimulation with its antagonist fulvestrant has opposite effects.Mechanistically,ERαinduces the expression of the histone 2A variant H2A.Z to restrict the engagement of the IFN-stimulated gene factor 3(ISGF3)complex to the promoters of ISGs and also interacts with STAT2 to disrupt the assembly of the ISGF3 complex.These two events mutually lead to the inhibition of ISG transcription induced by type I IFNs.In a xenograft mouse model,fulvestrant enhances the ability of IFN-βto suppress ERα^(+)breast tumor growth.Consistently,clinical data analysis reveals that ERα^(+)breast cancer patients with higher levels of ISGs exhibit higher long-term survival rates.Taken together,our findings suggest that ERαinhibits type I IFN response via two distinct mechanisms to promote breast carcinogenesis.展开更多
The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis(IAC).How this axis is regulated to modulate IAC remains unknown.Here,we show that the plasma membrane-associated E3 ubiquitin ligase...The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis(IAC).How this axis is regulated to modulate IAC remains unknown.Here,we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates STAT3 activation triggered by IL-6,as well as another IL-6 subfamily member,Oncostatin M(OSM).MARCH3 is associated with the IL-6 receptorα-chain(IL-6Rα)and its coreceptor gp130.Biochemical experiments indicated that MARCH3 mediates the polyubiquitination of IL-6Rαat K401 and gp130 at K849 following IL-6 stimulation,leading to their translocation to and degradation in lysosomes.MARCH3 deficiency increases IL-6-and OSM-triggered activation of STAT3 and induction of downstream effector genes in various cell types.MARCH3 deficiency enhances dextran sulfate sodium(DSS)-induced STAT3 activation,increases the expression of inflammatory cytokines,and exacerbates colitis,as well as azoxymethane(AOM)/DSS-induced colitis-associated cancer in mice.In addition,MARCH3 is downregulated in human colorectal cancer tissues and associated with poor survival across different cancer types.Our findings suggest that MARCH3 is a pivotal negative regulator of IL-6-induced STAT3 activation,inflammation,and inflammation-associated carcinogenesis.展开更多
The fungus Trichophyton schoenleinii(T.schoenleinii)is the causative agent of Trichophytosis and Tinea favosa of the scalp in certain regions of Eurasia and Africa.Hu-man innate immune system plays an important role i...The fungus Trichophyton schoenleinii(T.schoenleinii)is the causative agent of Trichophytosis and Tinea favosa of the scalp in certain regions of Eurasia and Africa.Hu-man innate immune system plays an important role in combating with various pathogens including fungi.The inflammasome is one of the most critical arms of host innate immunity,which is a protein complex controlling maturation of IL-1β.To clarify whether T.schoenleinii is able to activate the infl ammasome,we analyzed human monocytic cell line THP-1 for IL-1βproduction upon infec-tion with T.schoenleinii strain isolated from Tinea favosa patients,and rapid IL-1βsecretion from THP-1 cells was observed.Moreover,applying competitive inhibitors and gene specifi c silencing with shRNA,we found that T.sch-oenleinii induced IL-1βsecretion,ASC pyroptosome for-mation as well as caspase-1 activation were all dependent on NLRP3.Cathepsin B activity,ROS production and K+effl ux were required for the infl ammasome activation by T.schoenleinii.Our data thus reveal that the NLRP3 infl am-masome plays an important role in host defense against T.schoenleinii,and suggest that manipulating NLRP3 signaling can be a novel approach for control of diseases caused by T.schoenleinii infection.展开更多
Interleukin 5(IL-5)plays crucial roles in type 2-high asthma by mediating eosinophil maturation,activation,chemotaxis and survival.Inhibition of IL-5 signaling is considered a strategy for asthma treatment.Here,we ide...Interleukin 5(IL-5)plays crucial roles in type 2-high asthma by mediating eosinophil maturation,activation,chemotaxis and survival.Inhibition of IL-5 signaling is considered a strategy for asthma treatment.Here,we identified MARCH2 and MARCH3 as critical negative regulators of IL-5-triggered signaling.MARCH2 and MARCH3 associate with the IL-5 receptorαchain(IL-5Rα)and mediate its K27-linked polyubiquitination at K379 and K383,respectively,and its subsequent lysosomal degradation.Deficiency of MARCH2 or MARCH3 modestly increases the level of IL-5Rαand enhances IL-5-induced signaling,whereas double knockout of MARCH2/3 has a more dramatic effect.March2/3 double knockout markedly increases the proportions of eosinophils in the bone marrow and peripheral blood in mice.Double knockout of March2/3 aggravates ovalbumin(OVA)-induced eosinophilia and causes increased inflammatory cell infiltration,peribronchial mucus secretion and production of Th2 cytokines.Neutralization of Il-5 attenuates OVA-induced airway inflammation and the enhanced effects of March2/3 double deficiency.These findings suggest that MARCH2 and MARCH3 play redundant roles in targeting IL-5Rαfor degradation and negatively regulating allergic airway inflammation.展开更多
Pannexin-1(Panx1)forms nonselective large channel in cell plasma membrane and has been shown to be associated with NLRP3 inflammasome activation,ATP release and phagocytes recruitment.In the current study,by manipulat...Pannexin-1(Panx1)forms nonselective large channel in cell plasma membrane and has been shown to be associated with NLRP3 inflammasome activation,ATP release and phagocytes recruitment.In the current study,by manipulation of Panx1 expression in human myeloid cells and application of Panx1 defi cient mice,we failed to fi nd a correlation between Panx1 and NLRP3 infl ammasome activation,although an interaction between these two proteins was evident.However,in thioglycollate induced peritonitis,Panx1 defi cient mice showed much more phagocytes infiltration.Further analyses showed that mice defi cient for Panx1 exhibited enlarged F4/80^(low)Gr1-Ly6C-cell population in the peritonea.Our study thus reveals an important role for Panx1 in regulation of peritoneal cell population and peritonitis development.展开更多
SIGNAL 1 ALONE IS ENOUGH TO ACTIVATE THE NLRP3 INFLAMMAOSME IN HUMAN CELLS According to our current understanding,the NLR family,pyrin domain containing 3(NLRP3)infl ammasome activation is generally a two-step process...SIGNAL 1 ALONE IS ENOUGH TO ACTIVATE THE NLRP3 INFLAMMAOSME IN HUMAN CELLS According to our current understanding,the NLR family,pyrin domain containing 3(NLRP3)infl ammasome activation is generally a two-step process.The fi rst step is priming,in which pathogen associated molecular patterns(PAMPs)such as LPS or pro-inflammatory cytokines such as tumor necrosis factor-α(TNF-α)induced NF-κB activation provides synthesis of pro-IL-1βand NLRP3 proteins.This priming step is considered as signal 1,which makes the cell ready for a second strike to assemble the infl ammasome.Then danger signals such as ATP and MSU provide the signal 2 that promotes formation of the NLRP3 infl ammasome and activates caspase-1.Both of these 2 steps are required in mouse macrophages for the NLRP3 inflammasome activation(Dinarello,2007).展开更多
基金supported by grants from the State Key R&D Program of China(2022YFA1304900)the Fundamental Research Funds for the Central Universities(2042022dx0003)+2 种基金the National Natural Science Foundation of China(32188101,31830024)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071)the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(Grant No.ZNJC202205).
文摘Various cellular stress conditions trigger mitochondrial DNA(mtDNA)release from mitochondria into the cytosol.The released mtDNA is sensed by the cGAS-MITA/STING pathway,resulting in the induced expression of type I interferon and other effector genes.These processes contribute to the innate immune response to viral infection and other stress factors.The deregulation of these processes causes autoimmune diseases,inflammatory metabolic disorders and cancer.Therefore,the cGAS-MITA/STING pathway is a potential target for intervention in infectious,inflammatory and autoimmune diseases as well as cancer.In this review,we focus on the mechanisms underlying the mtDNA-triggered activation of the cGAS-MITA/STING pathway,the effects of the pathway under various physiological and pathological conditions,and advances in the development of drugs that target cGAS and MITA/STING.
基金supported by grants from the National Natural Science Foundation of China(32188101,31830024,31922021 and 32170713)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071).
文摘Upon viral infection, cytoplasmic pattern recognition receptors detect viral nucleic acids and activate the adaptor protein VISA/MAVS- or MITA/STING-mediated innate antiviral response. Whether and how the innate antiviral response is regulated by neuronal endocrine functions is unclear. Here, we show that viral infection reduced the serum levels of the β-adrenergic hormones epinephrine and norepinephrine as well as the cellular levels of their receptors ADRB1 and ADRB2. We further show that an increase in epinephrine/norepinephrine level inhibited the innate antiviral response in an ADRB1-/2-dependent manner. Mechanistically, epinephrine/norepinephrine stimulation activated the downstream kinase PKA, which catalyzed the phosphorylation of MITA at S241, S243 and T263, inhibiting MITA activation and suppressing the innate immune response to DNA virus. In addition, phosphorylation of VISA at T54 by PKA antagonized the innate immune response to RNA virus. These findings reveal the regulatory mechanisms of innate antiviral responses by epinephrine/norepinephrine and provide a possible explanation for increased host susceptibility to viral infection in stressful and anxiety-promoting situations.
基金supported by grants from the State Key R&D Program of China(2017YFA0505800)the National Natural Science Foundation of China(31830024,31922021,31771555,31630045,and 31801188)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071).
文摘Mitochondrial stress (mitostress) triggered by viral infection or mitochondrial dysfunction causes the release of mitochondrial DNA (mtDNA) into the cytosol and activates the cGAS-mediated innate immune response. The regulation of mtDNA release upon mitostress remains uncharacterized. Here, we identified mitochondria-associated vaccinia virus-related kinase 2 (VRK2) as a key regulator of this process. VRK2 deficiency inhibited the induction of antiviral genes and caused earlier and higher mortality in mice after viral infection. Upon viral infection, VRK2 associated with voltage-dependent anion channel 1 (VDAC1) and promoted VDAC1 oligomerization and mtDNA release, leading to the cGAS-mediated innate immune response. VRK2 was also required for mtDNA release and cGAS-mediated innate immunity triggered by nonviral factors that cause Ca^(2+) overload but was not required for the cytosolic nucleic acid-triggered innate immune response. Thus, VRK2 plays a crucial role in the mtDNA-triggered innate immune response and may be a potential therapeutic target for infectious and autoimmune diseases associated with mtDNA release.
基金This work was supported by grants from the State Key R&D Program of China(2017YFA0505800)the National Natural Science Foundation of China(31830024 and 32070775)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071).
文摘Interleukin-3(IL-3)is a hematopoietic growth factor and critical regulator of inflammatory response such as sepsis.IL-3 binds to IL-3 receptorα(IL-3Rα),which is then associated with IL-3Rβto initiate signaling.How IL-3-triggered physiological and pathological effects are regulated at the receptor level is unclear.Here,we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates IL-3-triggered signaling.MARCH3 is associated with IL-3Rα,mediates its K48-linked polyubiquitination at K377 and promotes its proteasomal degradation.MARCH3-deficiency promotes IL-3-triggered transcription of downstream effector genes and IL-3-induced expansion of myeloid cells.In the cecal ligation and puncture(CLP)model of sepsis,MARCH3-deficiency aggravates IL-3-ampified expression of inflammatory cytokines,organ damage and inflammatory death.Our findings suggest that regulation of IL-3Rαby MARCH3 plays an important role in IL-3-triggered physiological functions and inflammatory diseases.
基金supported by grants from the National Key R&D Program of China(2017YFA0505800)the National Natural Science Foundation of China(31830024 and 31630045)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2019-I2M-5-071).
文摘The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-mediator of interferon response factor 3 acti-vation/stimulator of interferon genes(MITA/STING)axis has emerged as a major pathway,which senses microbial or mislocated cellular DNA in the cytosol to trigger innate immune responses.cGAS senses cytosolic DNA without a preference of self-or nonself-DNA.How the cGAS-MITA/STING axis is inactivated upon nuclear envelope breakdown(NEBD)at mitotic entry in vertebrate cells to avoid self-DNA sensing remains unclear until very recently.In this review,we summarize the recent advances on how cGAS responds to chromosomes upon NEBD and the mechanisms involved in the inactivation of the cGAS-MITA/STING pathways in mitosis.
基金This work was supported by grants from the State Key R&D Program of China(2022YFA1304900)the National Natural Science Foundation of China(32188101,31830024,31922021,and 32170713)+1 种基金the Fundamental Research Funds for the Central Universities(2042022dx0003)Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2019-/2M-5-071).
文摘Estrogen receptorα(ERα)is an important driver and therapeutic target in∼70%of breast cancers.How ERαdrives breast carcinogenesis is not fully understood.In this study,we show that ERαis a negative regulator of type I interferon(IFN)response.Activation of ERαby its natural ligand estradiol inhibits IFN-β-induced transcription of downstream IFN-stimulated genes(ISGs),whereas ERαdeficiency or the stimulation with its antagonist fulvestrant has opposite effects.Mechanistically,ERαinduces the expression of the histone 2A variant H2A.Z to restrict the engagement of the IFN-stimulated gene factor 3(ISGF3)complex to the promoters of ISGs and also interacts with STAT2 to disrupt the assembly of the ISGF3 complex.These two events mutually lead to the inhibition of ISG transcription induced by type I IFNs.In a xenograft mouse model,fulvestrant enhances the ability of IFN-βto suppress ERα^(+)breast tumor growth.Consistently,clinical data analysis reveals that ERα^(+)breast cancer patients with higher levels of ISGs exhibit higher long-term survival rates.Taken together,our findings suggest that ERαinhibits type I IFN response via two distinct mechanisms to promote breast carcinogenesis.
基金This work was supported by grants from the National Key R&D Program of China(2017YFA0505800)the National Natural Science Foundation of China(31630045,31830024,31900556,and 32070775)+2 种基金the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071)the National Postdoctoral Program for Innovative Talents(BX20190255)the China Postdoctoral Science Foundation(2019M662706).
文摘The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis(IAC).How this axis is regulated to modulate IAC remains unknown.Here,we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates STAT3 activation triggered by IL-6,as well as another IL-6 subfamily member,Oncostatin M(OSM).MARCH3 is associated with the IL-6 receptorα-chain(IL-6Rα)and its coreceptor gp130.Biochemical experiments indicated that MARCH3 mediates the polyubiquitination of IL-6Rαat K401 and gp130 at K849 following IL-6 stimulation,leading to their translocation to and degradation in lysosomes.MARCH3 deficiency increases IL-6-and OSM-triggered activation of STAT3 and induction of downstream effector genes in various cell types.MARCH3 deficiency enhances dextran sulfate sodium(DSS)-induced STAT3 activation,increases the expression of inflammatory cytokines,and exacerbates colitis,as well as azoxymethane(AOM)/DSS-induced colitis-associated cancer in mice.In addition,MARCH3 is downregulated in human colorectal cancer tissues and associated with poor survival across different cancer types.Our findings suggest that MARCH3 is a pivotal negative regulator of IL-6-induced STAT3 activation,inflammation,and inflammation-associated carcinogenesis.
基金100 Talent Program of the Chinese Academy of Sciences,the National Natu-ral Science Foundation of China(Grant Nos.81160190,91029707,31170868,812111134 and 31100622)Shanghai Natural Science foun-dation(No.11ZR1442600)+1 种基金SA-SIBS Scholarship Program,Chinese Post-doctoral Science Foundation(No.20110490752)Post-doctoral research foundation of Shanghai Institutes for Biological Sciences(No.2011KIP513).
文摘The fungus Trichophyton schoenleinii(T.schoenleinii)is the causative agent of Trichophytosis and Tinea favosa of the scalp in certain regions of Eurasia and Africa.Hu-man innate immune system plays an important role in combating with various pathogens including fungi.The inflammasome is one of the most critical arms of host innate immunity,which is a protein complex controlling maturation of IL-1β.To clarify whether T.schoenleinii is able to activate the infl ammasome,we analyzed human monocytic cell line THP-1 for IL-1βproduction upon infec-tion with T.schoenleinii strain isolated from Tinea favosa patients,and rapid IL-1βsecretion from THP-1 cells was observed.Moreover,applying competitive inhibitors and gene specifi c silencing with shRNA,we found that T.sch-oenleinii induced IL-1βsecretion,ASC pyroptosome for-mation as well as caspase-1 activation were all dependent on NLRP3.Cathepsin B activity,ROS production and K+effl ux were required for the infl ammasome activation by T.schoenleinii.Our data thus reveal that the NLRP3 infl am-masome plays an important role in host defense against T.schoenleinii,and suggest that manipulating NLRP3 signaling can be a novel approach for control of diseases caused by T.schoenleinii infection.
基金This work was supported by grants from the National Natural Science Foundation of China(32188101,31830024 and 32070775)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071)the Fundamental Research Funds for the Central Universities.
文摘Interleukin 5(IL-5)plays crucial roles in type 2-high asthma by mediating eosinophil maturation,activation,chemotaxis and survival.Inhibition of IL-5 signaling is considered a strategy for asthma treatment.Here,we identified MARCH2 and MARCH3 as critical negative regulators of IL-5-triggered signaling.MARCH2 and MARCH3 associate with the IL-5 receptorαchain(IL-5Rα)and mediate its K27-linked polyubiquitination at K379 and K383,respectively,and its subsequent lysosomal degradation.Deficiency of MARCH2 or MARCH3 modestly increases the level of IL-5Rαand enhances IL-5-induced signaling,whereas double knockout of MARCH2/3 has a more dramatic effect.March2/3 double knockout markedly increases the proportions of eosinophils in the bone marrow and peripheral blood in mice.Double knockout of March2/3 aggravates ovalbumin(OVA)-induced eosinophilia and causes increased inflammatory cell infiltration,peribronchial mucus secretion and production of Th2 cytokines.Neutralization of Il-5 attenuates OVA-induced airway inflammation and the enhanced effects of March2/3 double deficiency.These findings suggest that MARCH2 and MARCH3 play redundant roles in targeting IL-5Rαfor degradation and negatively regulating allergic airway inflammation.
基金supported by grants from 100 Talent Program of the Chinese Academy of Sciences,National Natural Science Foundation of China(Grant Nos.91029707,31170868,812111134,and 31100622)Shanghai Natural Science foundation(11ZR1442600)+3 种基金Novo Nordisk-CAS Research Foundation(NN-CAS-2010-5(SIBS))SASIBS Scholarship Program,Chinese Post-doctoral Science Foundation(20110490752)Post-doctoral research foundation of Shanghai Institutes for Biological Sciences(2011KIP513)grants for excellent scientist from Ministry of Human Resources and Social Security of China.
文摘Pannexin-1(Panx1)forms nonselective large channel in cell plasma membrane and has been shown to be associated with NLRP3 inflammasome activation,ATP release and phagocytes recruitment.In the current study,by manipulation of Panx1 expression in human myeloid cells and application of Panx1 defi cient mice,we failed to fi nd a correlation between Panx1 and NLRP3 infl ammasome activation,although an interaction between these two proteins was evident.However,in thioglycollate induced peritonitis,Panx1 defi cient mice showed much more phagocytes infiltration.Further analyses showed that mice defi cient for Panx1 exhibited enlarged F4/80^(low)Gr1-Ly6C-cell population in the peritonea.Our study thus reveals an important role for Panx1 in regulation of peritoneal cell population and peritonitis development.
基金This work was supported by grants from 100 Talent Program of the Chinese Academy of Sciences,National Natural Science Foundation of China(Grant Nos.91029707,31170868,812111134,and 31100622)SASIBS Scholarship Program,Chinese Post-doctoral Science Foundation(No.20110490752)+2 种基金Post-doctoral research foundation of Shanghai Institutes for Biological Sciences(No.2011KIP513)the National Science and Technology Key Project(No.2012ZX10002007-003)as well as the CAS/SAFEA International Partnership Program for Creative Research Teams.
文摘SIGNAL 1 ALONE IS ENOUGH TO ACTIVATE THE NLRP3 INFLAMMAOSME IN HUMAN CELLS According to our current understanding,the NLR family,pyrin domain containing 3(NLRP3)infl ammasome activation is generally a two-step process.The fi rst step is priming,in which pathogen associated molecular patterns(PAMPs)such as LPS or pro-inflammatory cytokines such as tumor necrosis factor-α(TNF-α)induced NF-κB activation provides synthesis of pro-IL-1βand NLRP3 proteins.This priming step is considered as signal 1,which makes the cell ready for a second strike to assemble the infl ammasome.Then danger signals such as ATP and MSU provide the signal 2 that promotes formation of the NLRP3 infl ammasome and activates caspase-1.Both of these 2 steps are required in mouse macrophages for the NLRP3 inflammasome activation(Dinarello,2007).