The Experts below are selected from a list of 282 Experts worldwide ranked by ideXlab platform
David Artis - One of the best experts on this subject based on the ideXlab platform.
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Basophil derived il 4 promotes epicutaneous antigen sensitization concomitant with the development of food allergy
The Journal of Allergy and Clinical Immunology, 2018Co-Authors: Maryam Hussain, Kevin Walsh, Masato Kubo, David Artis, Brian S Kim, Loic Borcard, Maria Pena Rodriguez, Christoph Mueller, Mario NotiAbstract:Background Exaggerated thymic stromal lymphopoietin (TSLP) production and infiltration of Basophils are associated with the pathogenesis of atopic dermatitis (AD), a recognized risk factor for the development of food allergies. Although TSLP and Basophils have been implicated in promotion of food-induced allergic disorders in response to epicutaneous sensitization, the mechanisms by which TSLP-elicited Basophils guide the progression of allergic inflammation in the skin to distant mucosal sites, such as the gastrointestinal tract, are poorly understood. Objective We sought to test the role of Basophil-intrinsic IL-4 production in TH2 sensitization to food antigens in the skin and effector food-induced allergic responses in the gut. Methods Mice were epicutaneously sensitized with ovalbumin on an AD-like skin lesion, followed by intragastric antigen challenge to induce IgE-mediated food allergy. The requirement for Basophil-derived IL-4 production for TH2 polarization and the pathogenesis of IgE-mediated food allergy was assessed in vitro by using coculture experiments with naive T cells and in vivo by using Il4 3′UTR mice that selectively lack IL-4 production in Basophils. Results Epicutaneous food antigen sensitization is associated with infiltration of IL-4–competent innate immune cells to the skin, with Basophils and eosinophils representing the predominant populations. In contrast to Basophils, absence of eosinophils did not alter disease outcome. Coculture of IL-4–competent Basophils together with dendritic cells and naive T cells was sufficient to promote TH2 polarization in an IL-4–dependent manner in vitro, whereas absence of Basophil-intrinsic IL-4 production in vivo was associated with reduced food-induced allergic responses. Conclusion TSLP-elicited Basophils promote epicutaneous sensitization to food antigens and subsequent IgE-mediated food allergy through IL-4. Strategies to target the TSLP–Basophil–IL-4 axis in patients with AD might lead to innovative therapies that can prevent the progression of allergies to distant mucosal sites.
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Basophils and allergic inflammation
The Journal of Allergy and Clinical Immunology, 2013Co-Authors: Mark C Siracusa, Jonathan M Spergel, David ArtisAbstract:Basophils were discovered by Paul Ehrlich in 1879 and represent the least abundant granulocyte population in mammals. The relative rarity of Basophils and their phenotypic similarities with mast cells resulted in this cell lineage being historically overlooked, both clinically and experimentally. However, recent studies in human subjects and murine systems have shown that Basophils perform nonredundant effector functions and significantly contribute to the development and progression of T H 2 cytokine–mediated inflammation. Although the potential functions of murine and human Basophils have provoked some controversy, recent genetic approaches indicate that Basophils can migrate into lymphoid tissues and, in some circumstances, cooperate with other immune cells to promote optimal T H 2 cytokine responses in vivo . This article provides a brief historical perspective on Basophil-related research and discusses recent studies that have identified previously unappreciated molecules and pathways that regulate Basophil development, activation, and function in the context of allergic inflammation. Furthermore, we highlight the unique effector functions of Basophils and discuss their contributions to the development and pathogenesis of allergic inflammation in human disease. Finally, we discuss the therapeutic potential of targeting Basophils in preventing or alleviating the development and progression of allergic inflammation.
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thymic stromal lymphopoietin dependent Basophils promote th2 cytokine responses following intestinal helminth infection
Journal of Immunology, 2012Co-Authors: Mark C Siracusa, Paul R Giacomin, Michael R. Comeau, Kevin Walsh, Richard K Grencis, Masato Kubo, David ArtisAbstract:CD4+ Th2 cytokine responses promote the development of allergic inflammation and are critical for immunity to parasitic helminth infection. Recent studies highlighted that Basophils can promote Th2 cytokine-mediated inflammation and that phenotypic and functional heterogeneity exists between classical IL-3–elicited Basophils and thymic stromal lymphopoietin (TSLP)-elicited Basophils. However, whether distinct Basophil populations develop after helminth infection and their relative contributions to anti-helminth immune responses remain to be defined. After Trichinella spiralis infection of mice, we show that Basophil responses are rapidly induced in multiple tissue compartments, including intestinal-draining lymph nodes. Trichinella-induced Basophil responses were IL-3–IL-3R independent but critically dependent on TSLP–TSLPR interactions. Selective depletion of Basophils after Trichinella infection impaired infection-induced CD4+ Th2 cytokine responses, suggesting that TSLP-dependent Basophils augment Th2 cytokine responses after helminth infection. The identification and functional classification of TSLP-dependent Basophils in a helminth infection model, coupled with their recently described role in promoting atopic dermatitis, suggests that these cells may be a critical population in promoting Th2 cytokine-associated inflammation in a variety of inflammatory or infectious settings. Collectively, these data suggest that the TSLP–Basophil pathway may represent a new target in the design of therapeutic intervention strategies to promote or limit Th2 cytokine-dependent immunity and inflammation.
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Functional heterogeneity in the Basophil cell lineage.
Advances in immunology, 2012Co-Authors: Mark C Siracusa, Elia D. Tait Wojno, David ArtisAbstract:Abstract CD4 + T-helper type 2 (Th2) cells, characterized by their expression of interleukin (IL)-4, IL-5, IL-9, and IL-13, are required for immunity to helminth parasites and promote the pathological inflammation associated with asthma and allergic diseases. Recent reports from a number of laboratories have indicated that Basophils can influence the induction and/or effector stages of Th2 cytokine-mediated inflammation. However, the impact of Basophils appears to depend on the anatomical location and nature of the infectious or inflammatory stimulus. This review highlights the factors that regulate Basophil development and activation and describes known Basophil effector functions. Further, we discuss the recent identification of phenotypic and functional heterogeneity within murine and human Basophil populations and discuss how these findings may explain the context-dependent influence of Basophils on either the propagation, regulation, or effector phases of Th2 cytokine-associated inflammation.
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new insights into Basophil biology initiators regulators and effectors of type 2 inflammation
Annals of the New York Academy of Sciences, 2011Co-Authors: Mark C Siracusa, Michael R. Comeau, David ArtisAbstract:Recent studies indicate that Basophils perform essential functions in multiple models of Th2 cytokine-dependent immunity and inflammation. In addition to their role as late phase effector cells, Basophil populations can express MHC class II and costimulatory molecules, migrate into draining lymph nodes, present antigen to naive CD4(+) T cells, and promote Th2 cell differentiation. In this context, Basophils have been shown to contribute to the induction and propagation of Th2 cytokine responses following exposure to some helminth parasites or allergens. In this review, we discuss recent studies that provide new insights into Basophil development, regulation, and effector function. In addition, we discuss the ability of Basophils to act both independently and cooperatively with dendritic cells to support Th2 cytokine-mediated inflammation.
Hua Huang - One of the best experts on this subject based on the ideXlab platform.
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transcriptional regulation of mast cell and Basophil lineage commitment
Seminars in Immunopathology, 2016Co-Authors: Hua Huang, Yapeng LiAbstract:Basophils and mast cells have long been known to play critical roles in allergic disease and in immunity against parasitic infection. Accumulated evidence also supports that Basophils and mast cells have important roles in immune regulations, host defense against bacteria and viruses, and autoimmune diseases. However, origin and molecular regulation of Basophil and mast cell differentiation remain incompletely understood. In this review, we focus on recent advances in the understanding of origin and molecular regulation of mouse and human Basophil and mast cell development. A more complete understanding of how Basophils and mast cells develop at the molecular level will lead to development of interventions that are more effective in achieving long-term success.
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the stat5 gata2 pathway is critical in Basophil and mast cell differentiation and maintenance
Journal of Immunology, 2015Co-Authors: Bing Liu, Hua HuangAbstract:Transcription factor GATA binding protein 2 (GATA2) plays critical roles in hematopoietic stem cell survival and proliferation, granulocyte-monocyte progenitor differentiation, and Basophil and mast cell differentiation. However, precise roles of GATA2 in Basophil and mast cell differentiation and maintenance have not been delineated. We have identified GATA2 as an essential transcription factor in differentiation of newly identified common Basophil and mast cell progenitors into Basophils and mast cells. We observed Gata2 haploinsufficiency for mast cell differentiation, but not for Basophil differentiation. We examined the precise role of GATA2 in maintaining the expression of a wide range of genes that are important for performing Basophil or mast cell functions. The effects of GATA2 on gene expression were broadly based. We demonstrated that GATA2 was required for maintaining Fcer1a mRNA and FceRIα protein expression on both Basophils and mast cells, as well as for maintaining Kit mRNA and c-Kit protein expression on mast cells. GATA2 was required for histamine synthesis and was also critical for Il4 mRNA expression in Basophils and Il13 mRNA expression in mast cells. We demonstrate a STAT5-GATA2 connection, showing that the STAT5 transcription factor directly bound to the promoter and an intronic region of the Gata2 gene. Overexpression of the Gata2 gene was sufficient to direct Basophil and mast cell differentiation in the absence of the Stat5 gene. Our study reveals that the STAT5-GATA2 pathway is critical for Basophil and mast cell differentiation and maintenance.
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The STAT5–GATA2 Pathway Is Critical in Basophil and Mast Cell Differentiation and Maintenance
Journal of immunology (Baltimore Md. : 1950), 2015Co-Authors: Bing Liu, Hua HuangAbstract:Transcription factor GATA binding protein 2 (GATA2) plays critical roles in hematopoietic stem cell survival and proliferation, granulocyte-monocyte progenitor differentiation, and Basophil and mast cell differentiation. However, precise roles of GATA2 in Basophil and mast cell differentiation and maintenance have not been delineated. We have identified GATA2 as an essential transcription factor in differentiation of newly identified common Basophil and mast cell progenitors into Basophils and mast cells. We observed Gata2 haploinsufficiency for mast cell differentiation, but not for Basophil differentiation. We examined the precise role of GATA2 in maintaining the expression of a wide range of genes that are important for performing Basophil or mast cell functions. The effects of GATA2 on gene expression were broadly based. We demonstrated that GATA2 was required for maintaining Fcer1a mRNA and FceRIα protein expression on both Basophils and mast cells, as well as for maintaining Kit mRNA and c-Kit protein expression on mast cells. GATA2 was required for histamine synthesis and was also critical for Il4 mRNA expression in Basophils and Il13 mRNA expression in mast cells. We demonstrate a STAT5-GATA2 connection, showing that the STAT5 transcription factor directly bound to the promoter and an intronic region of the Gata2 gene. Overexpression of the Gata2 gene was sufficient to direct Basophil and mast cell differentiation in the absence of the Stat5 gene. Our study reveals that the STAT5-GATA2 pathway is critical for Basophil and mast cell differentiation and maintenance.
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Maintenanceand Mast Cell Differentiation and GATA2 Pathway Is Critical in − The STAT5
2015Co-Authors: Bing Liu, Hua HuangAbstract:Transcription factor GATA binding protein 2 (GATA2) plays critical roles in hematopoietic stem cell survival and proliferation,granulocyte–monocyte progenitor differentiation, and Basophil and mast cell differentiation. However, precise roles of GATA2 inBasophil and mast cell differentiation and maintenance have not been delineated. We have identified GATA2 as an essentialtranscription factor in differentiation of newly identified common Basophil and mast cell progenitors into Basophils and mast cells.We observed Gata2 haploinsufficiency for mast cell differentiation, but not for Basophil differentiation. We examined the preciserole of GATA2 in maintaining the expression of a wide range of genes that are important for performing Basophil or mast cellfunctions. The effects of GATA2 on gene expression were broadly based. We demonstrated that GATA2 was required for main-taining Fcer1a mRNA and Fc«RIa protein expression on both Basophils and mast cells, as well as for maintaining Kit mRNA andc-Kit protein expression on mast cells. GATA2 was required for histamine synthesis and was also critical for Il4 mRNA expressionin Basophils and Il13 mRNA expression in mast cells. We demonstrate a STAT5–GATA2 connection, showing that the STAT5transcription factor directly bound to the promoter and an intronic region of the Gata2 gene. Overexpression of the Gata2 genewas sufficient to direct Basophil and mast cell differentiation in the absence of the Stat5 gene. Our study reveals that the STAT5–GATA2 pathway is critical for Basophil and mast cell differentiation and maintenance. The Journal of Immunology, 2015, 194:000–000.
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il 3 induces Basophil expansion in vivo by directing granulocyte monocyte progenitors to differentiate into Basophil lineage restricted progenitors in the bone marrow and by increasing the number of Basophil mast cell progenitors in the spleen
Journal of Immunology, 2009Co-Authors: Keitaro Ohmori, Demin Wang, Jun Nishida, Zhengqi Wang, Kevin D Bunting, Hua HuangAbstract:Recent work has established important roles for Basophils in regulating immune responses. To exert their biological functions, Basophils need to be expanded to critical numbers. However, the mechanisms underlying Basophil expansion remain unclear. In this study, we established that IL-3 played an important role in the rapid and specific expansion of Basophils. We found that the IL-3 complex (IL-3 plus anti-IL-3 Ab) greatly facilitated the differentiation of GMPs into Basophil lineage-restricted progenitors (BaPs) but not into eosinophil lineage-restricted progenitors or mast cells in the bone marrow. We also found that the IL-3 complex treatment resulted in ∼4-fold increase in the number of Basophil/mast cell progenitors (BMCPs) in the spleen. IL-3-driven Basophil expansion depended on STAT5 signaling. We showed that GMPs but not common myeloid progenitors expressed low levels of IL-3 receptor. IL-3 receptor expression was dramatically up-regulated in BaPs but not eosinophil lineage-restricted progenitors. Approximately 38% of BMCPs expressed the IL-3Rα-chain. The up-regulated IL-3 receptor expression was not affected by IL-3 or STAT5. Our findings demonstrate that IL-3 induced specific expansion of Basophils by directing GMPs to differentiate into BaPs in the bone marrow and by increasing the number of BMCPs in the spleen.
Mark C Siracusa - One of the best experts on this subject based on the ideXlab platform.
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Basophils and allergic inflammation
The Journal of Allergy and Clinical Immunology, 2013Co-Authors: Mark C Siracusa, Jonathan M Spergel, David ArtisAbstract:Basophils were discovered by Paul Ehrlich in 1879 and represent the least abundant granulocyte population in mammals. The relative rarity of Basophils and their phenotypic similarities with mast cells resulted in this cell lineage being historically overlooked, both clinically and experimentally. However, recent studies in human subjects and murine systems have shown that Basophils perform nonredundant effector functions and significantly contribute to the development and progression of T H 2 cytokine–mediated inflammation. Although the potential functions of murine and human Basophils have provoked some controversy, recent genetic approaches indicate that Basophils can migrate into lymphoid tissues and, in some circumstances, cooperate with other immune cells to promote optimal T H 2 cytokine responses in vivo . This article provides a brief historical perspective on Basophil-related research and discusses recent studies that have identified previously unappreciated molecules and pathways that regulate Basophil development, activation, and function in the context of allergic inflammation. Furthermore, we highlight the unique effector functions of Basophils and discuss their contributions to the development and pathogenesis of allergic inflammation in human disease. Finally, we discuss the therapeutic potential of targeting Basophils in preventing or alleviating the development and progression of allergic inflammation.
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thymic stromal lymphopoietin dependent Basophils promote th2 cytokine responses following intestinal helminth infection
Journal of Immunology, 2012Co-Authors: Mark C Siracusa, Paul R Giacomin, Michael R. Comeau, Kevin Walsh, Richard K Grencis, Masato Kubo, David ArtisAbstract:CD4+ Th2 cytokine responses promote the development of allergic inflammation and are critical for immunity to parasitic helminth infection. Recent studies highlighted that Basophils can promote Th2 cytokine-mediated inflammation and that phenotypic and functional heterogeneity exists between classical IL-3–elicited Basophils and thymic stromal lymphopoietin (TSLP)-elicited Basophils. However, whether distinct Basophil populations develop after helminth infection and their relative contributions to anti-helminth immune responses remain to be defined. After Trichinella spiralis infection of mice, we show that Basophil responses are rapidly induced in multiple tissue compartments, including intestinal-draining lymph nodes. Trichinella-induced Basophil responses were IL-3–IL-3R independent but critically dependent on TSLP–TSLPR interactions. Selective depletion of Basophils after Trichinella infection impaired infection-induced CD4+ Th2 cytokine responses, suggesting that TSLP-dependent Basophils augment Th2 cytokine responses after helminth infection. The identification and functional classification of TSLP-dependent Basophils in a helminth infection model, coupled with their recently described role in promoting atopic dermatitis, suggests that these cells may be a critical population in promoting Th2 cytokine-associated inflammation in a variety of inflammatory or infectious settings. Collectively, these data suggest that the TSLP–Basophil pathway may represent a new target in the design of therapeutic intervention strategies to promote or limit Th2 cytokine-dependent immunity and inflammation.
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Functional heterogeneity in the Basophil cell lineage.
Advances in immunology, 2012Co-Authors: Mark C Siracusa, Elia D. Tait Wojno, David ArtisAbstract:Abstract CD4 + T-helper type 2 (Th2) cells, characterized by their expression of interleukin (IL)-4, IL-5, IL-9, and IL-13, are required for immunity to helminth parasites and promote the pathological inflammation associated with asthma and allergic diseases. Recent reports from a number of laboratories have indicated that Basophils can influence the induction and/or effector stages of Th2 cytokine-mediated inflammation. However, the impact of Basophils appears to depend on the anatomical location and nature of the infectious or inflammatory stimulus. This review highlights the factors that regulate Basophil development and activation and describes known Basophil effector functions. Further, we discuss the recent identification of phenotypic and functional heterogeneity within murine and human Basophil populations and discuss how these findings may explain the context-dependent influence of Basophils on either the propagation, regulation, or effector phases of Th2 cytokine-associated inflammation.
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tslp promotes interleukin 3 independent Basophil haematopoiesis and type 2 inflammation
Nature, 2011Co-Authors: Mark C Siracusa, Steven A Saenz, David A Hill, Brian S Kim, Mark B Headley, Travis A Doering, John E Wherry, Heidi K Jessup, Lori Siegel, Taku KambayashiAbstract:CD4(+) T-helper type 2 (T(H)2) cells, characterized by their expression of interleukin (IL)-4, IL-5, IL-9 and IL-13, are required for immunity to helminth parasites and promote the pathological inflammation associated with asthma and allergic diseases. Polymorphisms in the gene encoding the cytokine thymic stromal lymphopoietin (TSLP) are associated with the development of multiple allergic disorders in humans, indicating that TSLP is a critical regulator of T(H)2 cytokine-associated inflammatory diseases. In support of genetic analyses, exaggerated TSLP production is associated with asthma, atopic dermatitis and food allergies in patients, and studies in murine systems demonstrated that TSLP promotes T(H)2 cytokine-mediated immunity and inflammation. However, the mechanisms through which TSLP induces T(H)2 cytokine responses remain poorly defined. Here we demonstrate that TSLP promotes systemic Basophilia, that disruption of TSLP-TSLPR interactions results in defective Basophil responses, and that TSLPR-sufficient Basophils can restore T(H)2-cell-dependent immunity in vivo. TSLP acted directly on bone-marrow-resident progenitors to promote Basophil responses selectively. Critically, TSLP could elicit Basophil responses in both IL-3-IL-3R-sufficient and -deficient environments, and genome-wide transcriptional profiling and functional analyses identified heterogeneity between TSLP-elicited versus IL-3-elicited Basophils. Furthermore, activated human Basophils expressed TSLPR, and Basophils isolated from eosinophilic oesophagitis patients were distinct from classical Basophils. Collectively, these studies identify previously unrecognized heterogeneity within the Basophil cell lineage and indicate that expression of TSLP may influence susceptibility to multiple allergic diseases by regulating Basophil haematopoiesis and eliciting a population of functionally distinct Basophils that promote T(H)2 cytokine-mediated inflammation.
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new insights into Basophil biology initiators regulators and effectors of type 2 inflammation
Annals of the New York Academy of Sciences, 2011Co-Authors: Mark C Siracusa, Michael R. Comeau, David ArtisAbstract:Recent studies indicate that Basophils perform essential functions in multiple models of Th2 cytokine-dependent immunity and inflammation. In addition to their role as late phase effector cells, Basophil populations can express MHC class II and costimulatory molecules, migrate into draining lymph nodes, present antigen to naive CD4(+) T cells, and promote Th2 cell differentiation. In this context, Basophils have been shown to contribute to the induction and propagation of Th2 cytokine responses following exposure to some helminth parasites or allergens. In this review, we discuss recent studies that provide new insights into Basophil development, regulation, and effector function. In addition, we discuss the ability of Basophils to act both independently and cooperatively with dendritic cells to support Th2 cytokine-mediated inflammation.
Haruka Sasaki - One of the best experts on this subject based on the ideXlab platform.
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transcription factor irf8 plays a critical role in the development of murine Basophils and mast cells
Blood, 2015Co-Authors: Haruka Sasaki, Naoki Osato, Izumi Sasaki, Chika Kaneda, Shinichi Koizumi, Hideaki Sato, Hongsheng Wang, Akira Nishiyama, Daisuke Kurotaki, Tsuneyasu KaishoAbstract:Basophils and mast cells play critical roles in host defense against pathogens and allergic disorders. However, the molecular mechanism by which these cells are generated is not completely understood. Here we demonstrate that interferon regulatory factor-8 (IRF8), a transcription factor essential for the development of several myeloid lineages, also regulates Basophil and mast cell development. Irf8−/− mice displayed a severe reduction in Basophil counts, which was accounted for by the absence of pre-Basophil and mast cell progenitors (pre-BMPs). Although Irf8−/− mice retained peripheral tissue mast cells, remaining progenitors from Irf8−/− mice including granulocyte progenitors (GPs) were unable to efficiently generate either Basophils or mast cells, indicating that IRF8 also contributes to the development of mast cells. IRF8 appeared to function at the GP stage, because IRF8 was expressed in GPs, but not in Basophils, mast cells, and Basophil/mast cell-restricted progenitor cells. Furthermore, we demonstrate that GATA2, a transcription factor known to promote Basophil and mast cell differentiation, acts downstream of IRF8. These results shed light on the pathways and mechanism underlying the development of Basophils and mast cells.
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the transcription factor irf8 is a key transcription factor for Basophil development
Blood, 2013Co-Authors: Haruka Sasaki, Naoki Osato, Izumi Sasaki, Chika Kaneda, Herbert C. Morse, Hideaki Sato, Tsuneyasu Kaisho, Hiroyuki Aburatani, Akira Nishiyama, Keiko OzatoAbstract:Basophils are the rarest granulocytes circulating in the peripheral blood. They play critical roles in anti-parasite Th2-type immune responses and chronic allergic disorders. The developmental pathway for Basophils has been recently demonstrated; myeloid progenitors pass through common myeloid progenitors, granulocyte-monocyte progenitors, granulocyte-committed progenitors (GPs), and Basophil-committed progenitors (BaPs) in the bone marrow. BaPs then give rise to mature Basophils. However, our understanding of how this pathway is regulated remains still elusive. Interferon Regulatory Factor-8 (IRF8), a hematopoietic cell-specific IRF transcription factor, is essential for the development of monocytes, dendritic cells, and eosinophils, while it inhibits neutrophil differentiation. Its role in the development of Basophils has yet to be analyzed. In this study, we investigated whether IRF8 has any role in the development of the Basophil lineage. We found that Irf8 –/– mice displayed a severe reduction of Basophil counts in the bone marrow, peripheral blood and spleen compared to wild-type (WT) mice. Irf8 –/– mice retained GPs but lacked BaPs. Cell transfer experiments revealed that the defect of Basophil development in Irf8 –/– mice resides in bone marrow cells. We utilized IRF8-GFP chimera knock-in mice to examine IRF8 protein expression in the Basophil lineage at a single cell level. We found that GPs, but not BaPs and mature Basophils, expressed IRF8. Furthermore, purified Irf8 –/– GPs failed to efficiently give rise to Basophils in vitro . These results indicate that IRF8 acts at the stage of GPs in a cell-intrinsic manner. To understand the mechanism by which IRF8 promotes Basophil development, we performed transcriptome analysis of purified GPs from WT and Irf8 –/– mice by microarray. Because IRF8 is no more expressed in BaPs, we envisaged that IRF8 acts by inducing downstream transcription factors in GPs. The expression of several transcription factor genes such as Gata2 and Spib was reduced in Irf8 –/– GPs compared to WT GPs. Analysis of DNA motifs in the promoter regions of genes downregulated in Irf8 –/– GPs predicted that GATA transcription factor(s) may act downstream of IRF8. Indeed, retroviral transduction of GATA2, known to be essential for Basophil development, into Irf8 –/– hematopoietic progenitor cells rescued Basophil differentiation in vitro . On the other hand, Spib –/– mice showed no obvious defects in Basophil development. Taken together, these results suggest that the IRF8-GATA2 axis in GPs critically regulates Basophil development. Disclosures: No relevant conflicts of interest to declare.
Tsuneyasu Kaisho - One of the best experts on this subject based on the ideXlab platform.
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transcription factor irf8 plays a critical role in the development of murine Basophils and mast cells
Blood, 2015Co-Authors: Haruka Sasaki, Naoki Osato, Izumi Sasaki, Chika Kaneda, Shinichi Koizumi, Hideaki Sato, Hongsheng Wang, Akira Nishiyama, Daisuke Kurotaki, Tsuneyasu KaishoAbstract:Basophils and mast cells play critical roles in host defense against pathogens and allergic disorders. However, the molecular mechanism by which these cells are generated is not completely understood. Here we demonstrate that interferon regulatory factor-8 (IRF8), a transcription factor essential for the development of several myeloid lineages, also regulates Basophil and mast cell development. Irf8−/− mice displayed a severe reduction in Basophil counts, which was accounted for by the absence of pre-Basophil and mast cell progenitors (pre-BMPs). Although Irf8−/− mice retained peripheral tissue mast cells, remaining progenitors from Irf8−/− mice including granulocyte progenitors (GPs) were unable to efficiently generate either Basophils or mast cells, indicating that IRF8 also contributes to the development of mast cells. IRF8 appeared to function at the GP stage, because IRF8 was expressed in GPs, but not in Basophils, mast cells, and Basophil/mast cell-restricted progenitor cells. Furthermore, we demonstrate that GATA2, a transcription factor known to promote Basophil and mast cell differentiation, acts downstream of IRF8. These results shed light on the pathways and mechanism underlying the development of Basophils and mast cells.
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the transcription factor irf8 is a key transcription factor for Basophil development
Blood, 2013Co-Authors: Haruka Sasaki, Naoki Osato, Izumi Sasaki, Chika Kaneda, Herbert C. Morse, Hideaki Sato, Tsuneyasu Kaisho, Hiroyuki Aburatani, Akira Nishiyama, Keiko OzatoAbstract:Basophils are the rarest granulocytes circulating in the peripheral blood. They play critical roles in anti-parasite Th2-type immune responses and chronic allergic disorders. The developmental pathway for Basophils has been recently demonstrated; myeloid progenitors pass through common myeloid progenitors, granulocyte-monocyte progenitors, granulocyte-committed progenitors (GPs), and Basophil-committed progenitors (BaPs) in the bone marrow. BaPs then give rise to mature Basophils. However, our understanding of how this pathway is regulated remains still elusive. Interferon Regulatory Factor-8 (IRF8), a hematopoietic cell-specific IRF transcription factor, is essential for the development of monocytes, dendritic cells, and eosinophils, while it inhibits neutrophil differentiation. Its role in the development of Basophils has yet to be analyzed. In this study, we investigated whether IRF8 has any role in the development of the Basophil lineage. We found that Irf8 –/– mice displayed a severe reduction of Basophil counts in the bone marrow, peripheral blood and spleen compared to wild-type (WT) mice. Irf8 –/– mice retained GPs but lacked BaPs. Cell transfer experiments revealed that the defect of Basophil development in Irf8 –/– mice resides in bone marrow cells. We utilized IRF8-GFP chimera knock-in mice to examine IRF8 protein expression in the Basophil lineage at a single cell level. We found that GPs, but not BaPs and mature Basophils, expressed IRF8. Furthermore, purified Irf8 –/– GPs failed to efficiently give rise to Basophils in vitro . These results indicate that IRF8 acts at the stage of GPs in a cell-intrinsic manner. To understand the mechanism by which IRF8 promotes Basophil development, we performed transcriptome analysis of purified GPs from WT and Irf8 –/– mice by microarray. Because IRF8 is no more expressed in BaPs, we envisaged that IRF8 acts by inducing downstream transcription factors in GPs. The expression of several transcription factor genes such as Gata2 and Spib was reduced in Irf8 –/– GPs compared to WT GPs. Analysis of DNA motifs in the promoter regions of genes downregulated in Irf8 –/– GPs predicted that GATA transcription factor(s) may act downstream of IRF8. Indeed, retroviral transduction of GATA2, known to be essential for Basophil development, into Irf8 –/– hematopoietic progenitor cells rescued Basophil differentiation in vitro . On the other hand, Spib –/– mice showed no obvious defects in Basophil development. Taken together, these results suggest that the IRF8-GATA2 axis in GPs critically regulates Basophil development. Disclosures: No relevant conflicts of interest to declare.