Hepatic ischemia–reperfusion injury(HIRI)is an important cause of liver injury following liver transplantation and major resections,and neutrophils are the key effector cells in HIRI.Double-negative T regulatory cell...Hepatic ischemia–reperfusion injury(HIRI)is an important cause of liver injury following liver transplantation and major resections,and neutrophils are the key effector cells in HIRI.Double-negative T regulatory cells(DNT)are increasingly recognized as having critical regulatory functions in the immune system.Whether DNT expresses distinct immunoregulatory mechanisms to modulate neutrophils,as in HIRI,remains largely unknown.In this study,we found that murine and human DNT highly expressed CD39that protected DNT from extracellular ATP-induced apoptosis and generated adenosine in tandem with CD73,to induce high levels of neutrophil apoptosis.Furthermore,extracellular adenosine enhanced DNT survival and suppressive function by upregulating survivin and NKG2D expression via the A2AR/pAKT/FOXO1 signaling pathway.Adoptive transfer of DNT ameliorated HIRI in mice through the inhibition of neutrophils in a CD39-dependent manner.Lastly,the adoptive transfer of A2ar^(-/-)DNT validated the importance of adenosine/A2AR signaling,in promoting DNT survival and immunomodulatory function to protect against HIRI in vivo.In conclusion,purinergic signaling is crucial for DNT homeostasis in HIRI.Augmentation of CD39 or activation of A2AR signaling in DNT may provide novel therapeutic strategies to target innate immune disorders.展开更多
Autoimmune hepatitis (AIH) is an important disorder that predominantly results in inflammatory liver disease in genetically predisposed women.The clinicopathological picture is characterized by symptoms associated wit...Autoimmune hepatitis (AIH) is an important disorder that predominantly results in inflammatory liver disease in genetically predisposed women.The clinicopathological picture is characterized by symptoms associated with both systemic inflammation and hepatic dysfunction,and with increased serum aminotransferases,elevated IgG,autoantibodies,and interface hepatitis on liver biopsy.AIH usually results in liver injury as a consequence of chronic hepatitis and cirrhosis.However,rarely,patients may present with fulminant liver failure.Early diagnosis is important in all instances because the disease can be highly responsive to immunosuppressive therapeutic options.Left untreated,the disease is associated with high morbidity and mortality.Here we provide an overview of the current state of knowledge on AIH and summarize the treatment options for this serious condition in adults.We also discuss the pathogenesis of the disease as a possible consequence of autoimmunity and the breakdown of hepatic tolerance.We focus on regulatory T cell impairments as a consequence of changes in CD39 ectonucleotidase expression and altered purinergic signaling.Further understanding of hepatic tolerance may aid in the development of specific and well-tolerated therapies for AIH.展开更多
Human cells contain two types of adenosine deaminases(ADA)each with unique properties:ADA1,which is present in all cells where it modulates intracellular functions and extracellular signaling,and ADA2,which is secrete...Human cells contain two types of adenosine deaminases(ADA)each with unique properties:ADA1,which is present in all cells where it modulates intracellular functions and extracellular signaling,and ADA2,which is secreted by immune cells.The exact intracellular functions of ADA2 remain undetermined and less defined than those of ADA1.ADA2 has distinct characteristics,such as low adenosine affinity,heparin-binding ability,and putative lysosomal entry.Here,we confirm that ADA2 is a lysosomal protein that binds toll-like receptor 9(TLR9)agonists,specifically CpG oligodeoxynucleotides(CpG ODNs).We show that interferon-alpha(IFN-α)is secreted in response to TLR9 activation by CpG ODNs and natural DNA and markedly increases when ADA2 expression is downregulated in plasmacytoid dendritic cells(pDCs).Additionally,the pretreatment of pDCs with RNA further stimulates IFN-αsecretion by pDCs after activation with CpG ODNs.Our findings indicate that ADA2 regulates TLR9 responses to DNA in activated pDCs.In conclusion,decreasing ADA2 expression or blocking it with specific oligonucleotides can enhance IFN-αsecretion from pDCs,improving immune responses against intracellular infections and cancer.展开更多
基金supported by the grants from the National Natural Science Foundation of China(81970503,82100670,82202021and 82270606)Chinese Institutes for Medical Research+7 种基金Beijing(CX24PY16)R&D Program of Beijing Municipal Education Commission(KZ202210025036)Beijing Municipal Administration of Hospitals’Ascent Plan(DFL20220103)Beijing Nova Program(Z211100002121036)Youth Beijing Scholar(035)and the Reform and Development Program of Beijing Institute of Respiratory Medicine(Ggyfz202403)Generation of reagents and mutant mice are also supported by the National Institutes of Health(R01 DK108894R21 CA164970 and R21 CA221702)Department of Defense Award W81XWH-16-0464。
文摘Hepatic ischemia–reperfusion injury(HIRI)is an important cause of liver injury following liver transplantation and major resections,and neutrophils are the key effector cells in HIRI.Double-negative T regulatory cells(DNT)are increasingly recognized as having critical regulatory functions in the immune system.Whether DNT expresses distinct immunoregulatory mechanisms to modulate neutrophils,as in HIRI,remains largely unknown.In this study,we found that murine and human DNT highly expressed CD39that protected DNT from extracellular ATP-induced apoptosis and generated adenosine in tandem with CD73,to induce high levels of neutrophil apoptosis.Furthermore,extracellular adenosine enhanced DNT survival and suppressive function by upregulating survivin and NKG2D expression via the A2AR/pAKT/FOXO1 signaling pathway.Adoptive transfer of DNT ameliorated HIRI in mice through the inhibition of neutrophils in a CD39-dependent manner.Lastly,the adoptive transfer of A2ar^(-/-)DNT validated the importance of adenosine/A2AR signaling,in promoting DNT survival and immunomodulatory function to protect against HIRI in vivo.In conclusion,purinergic signaling is crucial for DNT homeostasis in HIRI.Augmentation of CD39 or activation of A2AR signaling in DNT may provide novel therapeutic strategies to target innate immune disorders.
文摘Autoimmune hepatitis (AIH) is an important disorder that predominantly results in inflammatory liver disease in genetically predisposed women.The clinicopathological picture is characterized by symptoms associated with both systemic inflammation and hepatic dysfunction,and with increased serum aminotransferases,elevated IgG,autoantibodies,and interface hepatitis on liver biopsy.AIH usually results in liver injury as a consequence of chronic hepatitis and cirrhosis.However,rarely,patients may present with fulminant liver failure.Early diagnosis is important in all instances because the disease can be highly responsive to immunosuppressive therapeutic options.Left untreated,the disease is associated with high morbidity and mortality.Here we provide an overview of the current state of knowledge on AIH and summarize the treatment options for this serious condition in adults.We also discuss the pathogenesis of the disease as a possible consequence of autoimmunity and the breakdown of hepatic tolerance.We focus on regulatory T cell impairments as a consequence of changes in CD39 ectonucleotidase expression and altered purinergic signaling.Further understanding of hepatic tolerance may aid in the development of specific and well-tolerated therapies for AIH.
文摘Human cells contain two types of adenosine deaminases(ADA)each with unique properties:ADA1,which is present in all cells where it modulates intracellular functions and extracellular signaling,and ADA2,which is secreted by immune cells.The exact intracellular functions of ADA2 remain undetermined and less defined than those of ADA1.ADA2 has distinct characteristics,such as low adenosine affinity,heparin-binding ability,and putative lysosomal entry.Here,we confirm that ADA2 is a lysosomal protein that binds toll-like receptor 9(TLR9)agonists,specifically CpG oligodeoxynucleotides(CpG ODNs).We show that interferon-alpha(IFN-α)is secreted in response to TLR9 activation by CpG ODNs and natural DNA and markedly increases when ADA2 expression is downregulated in plasmacytoid dendritic cells(pDCs).Additionally,the pretreatment of pDCs with RNA further stimulates IFN-αsecretion by pDCs after activation with CpG ODNs.Our findings indicate that ADA2 regulates TLR9 responses to DNA in activated pDCs.In conclusion,decreasing ADA2 expression or blocking it with specific oligonucleotides can enhance IFN-αsecretion from pDCs,improving immune responses against intracellular infections and cancer.
