We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma.Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly(I:C)/LyoVec or infection-rela...We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma.Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly(I:C)/LyoVec or infection-related cytokine TNF-αto induce expression of cytokines/chemokines/adhesion molecules.House dust mite(HDM)-induced allergic asthma and humanized allergic asthma NOD/SCID murine models were established to assess anti-inflammatory mechanisms in vivo.IL-38 significantly inhibited induced proinflammatory IL-6,IL-1β,CCL5,and CXCL10 production,and antiviral interferon-βand intercellular adhesion molecule-1 expression in the coculture system.Mass cytometry and RNA-sequencing analysis revealed that IL-38 could antagonize the activation of the intracellular STAT1,STAT3,p38 MAPK,ERK1/2,and NF-κB pathways,and upregulate the expression of the host defense-related gene POU2AF1 and anti-allergic response gene RGS13.Intraperitoneal injection of IL-38 into HDM-induced allergic asthma mice could ameliorate airway hyperreactivity by decreasing the accumulation of eosinophils in the lungs and inhibiting the expression of the Th2-related cytokines IL-4,IL-5,and IL-13 in the bronchoalveolar lavage fluid(BALF)and lung homogenates.Histological examination indicated lung inflammation was alleviated by reductions in cell infiltration and goblet cell hyperplasia,together with reduced Th2,Th17,and innate lymphoid type 2 cell numbers but increased proportions of regulatory T cells in the lungs,spleen,and lymph nodes.IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice,together with significantly decreased CCR3^(+) eosinophil numbers in the BALF and lungs,and a reduced percentage of human CD4^(+)CRTH2^(+)Th2 cells in the lungs and mediastinal lymph nodes.Together,our results demonstrated the anti-inflammatory mechanisms of IL-38 and provided a basis for the development of a regulatory cytokine-based treatment for allergic asthma.展开更多
ILC2s are implicated in asthma pathogenesis, but little is known about the mechanisms underlying their accumulation in airways.We investigated the time course of ILC2 accumulation in different tissues in murine models...ILC2s are implicated in asthma pathogenesis, but little is known about the mechanisms underlying their accumulation in airways.We investigated the time course of ILC2 accumulation in different tissues in murine models of asthma induced by a serial per-nasalchallenge with ovalbumin (OVA), house dust mice (HDM), IL-25 and IL-33 and explored the potential roles of ILC2-attractingchemokines in this phenomenon. Flow cytometry was used to enumerate ILC2s at various time points. The effects of cytokines andchemokines on ILC2 migration were measured in vitro using a chemotaxis assay and in vivo using small animal imaging. Comparedwith saline and OVA challenge, both IL-25 and IL-33 challenge alone induced significant accumulation of ILC2s in the mediastinallymph nodes, lung tissue and bronchoalveolar lavage fluid of challenged animals, but with a distinct potency and kinetics. In vitro,IL-33 and CXCL16, but not IL-25 or CCL25, directly induced ILC2 migration. Small animal in vivo imaging further confirmed that asingle intranasal provocation with IL-33 or CXCL16 was sufficient to induce the accumulation of ILC2s in the lungs followinginjection via the tail vein. Moreover, IL-33-induced ILC2 migration involved the activation of ERK1/2, p38, Akt, JNK and NF-κB, whileCXCL16-induced ILC2 migration involved the activation of ERK1/2, p38 and Akt. These data support the hypothesis that epitheliumderived IL-25 and IL-33 induce lung accumulation of ILC2s, while IL-33 exerts a direct chemotactic effect in this process. AlthoughILC2s express the chemokine receptors CXCR6 and CCR9, only CXCL16, the ligand of CXCR6, exhibits a direct chemoattractanteffect.展开更多
Viral hepatitis is still a public health problem affecting several million people around the world.Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection.However,the role of neutr...Viral hepatitis is still a public health problem affecting several million people around the world.Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection.However,the role of neutrophils in viral infection is not fully understood.By using a mouse model of lymphocytic choriomeningitis virus infection-induced viral hepatitis,we observed increased neutrophil recruitment in the liver accompanied by enhanced CD8+T-cell responses.Liver neutrophils expressed high levels of immunomodulatory cytokines,such as C-X-C chemokine ligand 2,arginase-1,inducible nitric oxide synthase and interleukin(IL)-10,demonstrating immunosuppressive properties.Depletion of neutrophils in vivo by a neutralizing antibody resulted in the exacerbation of liver injury and the promotion of T-cell responses at the immune contraction stage.IL-33 significantly induced neutrophil recruitment in the liver and attenuated liver injury by limiting effector T-cell accumulation.Mechanistically,we found that IL-33 promoted the expression of arginase-1 in neutrophils through the type 2 innate lymphoid cell(ILC2)-derived IL-13.Additionally,IL-13 increased the inhibitory effect of neutrophils on CD8+T-cell proliferation in vitro,partially through arginase-1.Finally,we found that IL-13 induced arginase-1 expression,depending on signal transducer and activator of transcription factor 6(STAT6)signaling.Therefore,IL-33 induced immunosuppressive neutrophils via an ILC2/IL-13/STAT6 axis.Collectively,our findings shed new light on the mechanisms associated with IL-33-triggered neutrophils in the liver and suggest potential targets for therapeutic investigation in viral hepatitis.展开更多
Group 2 innate lymphoid cells(ILC2s)play important tissue resident roles in anti-parasite immunity,allergic immune response,tissue homeostasis,and tumor immunity.ILC2s are considered tissue resident cells with little ...Group 2 innate lymphoid cells(ILC2s)play important tissue resident roles in anti-parasite immunity,allergic immune response,tissue homeostasis,and tumor immunity.ILC2s are considered tissue resident cells with little proliferation at steady state.Recent studies have shown that a subset of small intestinal ILC2s could leave their residing tissues,circulate and migrate to different organs,including lung,liver,mesenteric LN and spleen,upon activation.However,it remains unknown whether other ILC populations with migratory behavior exist.In this study,we find two major colon ILC2 populations with potential to migrate to the lung in response to IL-25 stimulation.One subset expresses IL-17A and resembles inflammatory ILC2s(iILC2s)but lacks CD27 expression,whereas the other expresses CD27 but not IL-17A.In addition,the IL-17A^(+)ILC2s express lower levels of CD127,CD25,and ST2 than CD27^(+)ILC2s,which express higher levels of IL-5 and IL-13.Surprisingly,we found that both colon ILC2 populations still maintained their colonic features of preferential expression of IL-17A and CD27,IL-5/IL-13,respectively.Together,our study identifies two migratory colon ILC2 subsets with unique surface markers and cytokine profiles which are critical in regulating lung and colon immunity and homeostasis.展开更多
基金supported by Direct Grant for Research 2016/2017 and 2018/2019(Medicine Panel),project codes 4054327 and 4054391,respectivelyThe Chinese University of Hong Kong,Hong Kong,and Grant from Hong Kong Institute of Allergy 2018/2019(project code:6904815)+1 种基金supported in part by grants from the University of Macao(MYRG 2018-00033-FHS)the Macao Science and Technology Development Fund(FDCT102/2015/A3)to E.C.
文摘We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma.Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly(I:C)/LyoVec or infection-related cytokine TNF-αto induce expression of cytokines/chemokines/adhesion molecules.House dust mite(HDM)-induced allergic asthma and humanized allergic asthma NOD/SCID murine models were established to assess anti-inflammatory mechanisms in vivo.IL-38 significantly inhibited induced proinflammatory IL-6,IL-1β,CCL5,and CXCL10 production,and antiviral interferon-βand intercellular adhesion molecule-1 expression in the coculture system.Mass cytometry and RNA-sequencing analysis revealed that IL-38 could antagonize the activation of the intracellular STAT1,STAT3,p38 MAPK,ERK1/2,and NF-κB pathways,and upregulate the expression of the host defense-related gene POU2AF1 and anti-allergic response gene RGS13.Intraperitoneal injection of IL-38 into HDM-induced allergic asthma mice could ameliorate airway hyperreactivity by decreasing the accumulation of eosinophils in the lungs and inhibiting the expression of the Th2-related cytokines IL-4,IL-5,and IL-13 in the bronchoalveolar lavage fluid(BALF)and lung homogenates.Histological examination indicated lung inflammation was alleviated by reductions in cell infiltration and goblet cell hyperplasia,together with reduced Th2,Th17,and innate lymphoid type 2 cell numbers but increased proportions of regulatory T cells in the lungs,spleen,and lymph nodes.IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice,together with significantly decreased CCR3^(+) eosinophil numbers in the BALF and lungs,and a reduced percentage of human CD4^(+)CRTH2^(+)Th2 cells in the lungs and mediastinal lymph nodes.Together,our results demonstrated the anti-inflammatory mechanisms of IL-38 and provided a basis for the development of a regulatory cytokine-based treatment for allergic asthma.
基金the National Natural Science Foundation of China(81373177,81471594,and 81700026).
文摘ILC2s are implicated in asthma pathogenesis, but little is known about the mechanisms underlying their accumulation in airways.We investigated the time course of ILC2 accumulation in different tissues in murine models of asthma induced by a serial per-nasalchallenge with ovalbumin (OVA), house dust mice (HDM), IL-25 and IL-33 and explored the potential roles of ILC2-attractingchemokines in this phenomenon. Flow cytometry was used to enumerate ILC2s at various time points. The effects of cytokines andchemokines on ILC2 migration were measured in vitro using a chemotaxis assay and in vivo using small animal imaging. Comparedwith saline and OVA challenge, both IL-25 and IL-33 challenge alone induced significant accumulation of ILC2s in the mediastinallymph nodes, lung tissue and bronchoalveolar lavage fluid of challenged animals, but with a distinct potency and kinetics. In vitro,IL-33 and CXCL16, but not IL-25 or CCL25, directly induced ILC2 migration. Small animal in vivo imaging further confirmed that asingle intranasal provocation with IL-33 or CXCL16 was sufficient to induce the accumulation of ILC2s in the lungs followinginjection via the tail vein. Moreover, IL-33-induced ILC2 migration involved the activation of ERK1/2, p38, Akt, JNK and NF-κB, whileCXCL16-induced ILC2 migration involved the activation of ERK1/2, p38 and Akt. These data support the hypothesis that epitheliumderived IL-25 and IL-33 induce lung accumulation of ILC2s, while IL-33 exerts a direct chemotactic effect in this process. AlthoughILC2s express the chemokine receptors CXCR6 and CCR9, only CXCL16, the ligand of CXCR6, exhibits a direct chemoattractanteffect.
基金in part,by grants from the NIH(AI109100 and AI126371 to JS)PY was a visiting scientist partially supported by the Department of Infectious Diseases,Xiangya Hospital,China and the Natural Science Foundation of Hunan Province(no.14JJ6003)DMKY and ZK were recipients of summer internships from an NIAID T35 training grant(AI078878,PI:LS).
文摘Viral hepatitis is still a public health problem affecting several million people around the world.Neutrophils are polymorphonuclear cells that have a critical role in antibacterial infection.However,the role of neutrophils in viral infection is not fully understood.By using a mouse model of lymphocytic choriomeningitis virus infection-induced viral hepatitis,we observed increased neutrophil recruitment in the liver accompanied by enhanced CD8+T-cell responses.Liver neutrophils expressed high levels of immunomodulatory cytokines,such as C-X-C chemokine ligand 2,arginase-1,inducible nitric oxide synthase and interleukin(IL)-10,demonstrating immunosuppressive properties.Depletion of neutrophils in vivo by a neutralizing antibody resulted in the exacerbation of liver injury and the promotion of T-cell responses at the immune contraction stage.IL-33 significantly induced neutrophil recruitment in the liver and attenuated liver injury by limiting effector T-cell accumulation.Mechanistically,we found that IL-33 promoted the expression of arginase-1 in neutrophils through the type 2 innate lymphoid cell(ILC2)-derived IL-13.Additionally,IL-13 increased the inhibitory effect of neutrophils on CD8+T-cell proliferation in vitro,partially through arginase-1.Finally,we found that IL-13 induced arginase-1 expression,depending on signal transducer and activator of transcription factor 6(STAT6)signaling.Therefore,IL-33 induced immunosuppressive neutrophils via an ILC2/IL-13/STAT6 axis.Collectively,our findings shed new light on the mechanisms associated with IL-33-triggered neutrophils in the liver and suggest potential targets for therapeutic investigation in viral hepatitis.
基金supported by the National Natural Science Foundation of China(31930035,91942311,32061143028)Shanghai Science and Technology Commission(20410714000)+1 种基金the National Key Research and Developmental Program of China(2021YFA1301400)generous support from Flow cytometry Core and Sequencing Core at Shanghai Institute of Immunology and animal facility of Shanghai Jiao Tong University School of Medicine。
文摘Group 2 innate lymphoid cells(ILC2s)play important tissue resident roles in anti-parasite immunity,allergic immune response,tissue homeostasis,and tumor immunity.ILC2s are considered tissue resident cells with little proliferation at steady state.Recent studies have shown that a subset of small intestinal ILC2s could leave their residing tissues,circulate and migrate to different organs,including lung,liver,mesenteric LN and spleen,upon activation.However,it remains unknown whether other ILC populations with migratory behavior exist.In this study,we find two major colon ILC2 populations with potential to migrate to the lung in response to IL-25 stimulation.One subset expresses IL-17A and resembles inflammatory ILC2s(iILC2s)but lacks CD27 expression,whereas the other expresses CD27 but not IL-17A.In addition,the IL-17A^(+)ILC2s express lower levels of CD127,CD25,and ST2 than CD27^(+)ILC2s,which express higher levels of IL-5 and IL-13.Surprisingly,we found that both colon ILC2 populations still maintained their colonic features of preferential expression of IL-17A and CD27,IL-5/IL-13,respectively.Together,our study identifies two migratory colon ILC2 subsets with unique surface markers and cytokine profiles which are critical in regulating lung and colon immunity and homeostasis.
