It is well known that group 2 innate lymphoid cells(ILC2s)are enriched in mucosal tissues and respond to epithelial cell-derived cytokines,initiating and maintaining type 2 inflammation.Although an increased number of...It is well known that group 2 innate lymphoid cells(ILC2s)are enriched in mucosal tissues and respond to epithelial cell-derived cytokines,initiating and maintaining type 2 inflammation.Although an increased number of ILC2s has been observed at sites of allergic inflammation and during helminth infection,some studies have shown that ILC2s are largely tissue-resident cells seeded in the tissue early in life.展开更多
Innate lymphoid cells are predominantly tissue-resident immune cells that have diverse functions similar to T-cell subsets and regulate tissue homeostasis and innate immunity without specific antigen recognition. Prev...Innate lymphoid cells are predominantly tissue-resident immune cells that have diverse functions similar to T-cell subsets and regulate tissue homeostasis and innate immunity without specific antigen recognition. Previous studies have reported the important roles of type 2 innate lymphoid cells (ILC2s) in allergic inflammation.展开更多
Group 2 innate lymphoid cells(ILC2s)are a subset of ILCs that lack T and B-cell antigen receptors[1].ILC2s share similarities with CD4+T helper 2 cells(Th2)in transcription factor GATA3 expression and signature cytoki...Group 2 innate lymphoid cells(ILC2s)are a subset of ILCs that lack T and B-cell antigen receptors[1].ILC2s share similarities with CD4+T helper 2 cells(Th2)in transcription factor GATA3 expression and signature cytokines production,such as IL-5 and IL-13[1].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
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
文摘It is well known that group 2 innate lymphoid cells(ILC2s)are enriched in mucosal tissues and respond to epithelial cell-derived cytokines,initiating and maintaining type 2 inflammation.Although an increased number of ILC2s has been observed at sites of allergic inflammation and during helminth infection,some studies have shown that ILC2s are largely tissue-resident cells seeded in the tissue early in life.
基金in part,by AMED(grant numbers JP20fk0108129,JP21fk0108129h0702,and JP21lm0203007)a GSK Research grant(grant number A-32),JSPS KAKENHI(grant numbers JP21K16118 and JP21K08194)+4 种基金the Smoking Research Foundation(grant number 2021Y007)the Takeda Science Foundation,the Uehara Memorial Foundation(grant number 202110055)the MSD Life Science Foundation(grant number RA-026)the Japanese Respiratory Society Boehringer Ingelheim Research Grant Programthe Japan Intractable Diseases(Nanbyo)Research Foundation(grant number 2020B02).
文摘Innate lymphoid cells are predominantly tissue-resident immune cells that have diverse functions similar to T-cell subsets and regulate tissue homeostasis and innate immunity without specific antigen recognition. Previous studies have reported the important roles of type 2 innate lymphoid cells (ILC2s) in allergic inflammation.
基金This work was supported by grants 2020YFA0509103 and 2019YFA0802502 to JQ from the Ministry of Science and Technology of China,grants 32022027 and 31970860 to JQ from the National Natural Science Foundation of China and grants 22ZR1481800 and 20ZR1466900 to JQ from Shanghai Science and Technology Committee(STCSM).
文摘Group 2 innate lymphoid cells(ILC2s)are a subset of ILCs that lack T and B-cell antigen receptors[1].ILC2s share similarities with CD4+T helper 2 cells(Th2)in transcription factor GATA3 expression and signature cytokines production,such as IL-5 and IL-13[1].
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.
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.
