The Experts below are selected from a list of 2955 Experts worldwide ranked by ideXlab platform
Steven F. Ziegler - One of the best experts on this subject based on the ideXlab platform.
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Thymic Stromal Lymphopoietin improves survival and reduces inflammation in sepsis
American Journal of Respiratory Cell and Molecular Biology, 2016Co-Authors: Steven F. Ziegler, Hongwei Han, Adrian M Piliponsky, Asha Lahiri, Phuong Truong, Morgan Clauson, Nicholas J ShubinAbstract:The mechanisms that contribute to homeostasis of the immune system in sepsis are largely unknown. One study suggests a potential detrimental role for Thymic Stromal Lymphopoietin (TSLP) in sepsis; however, the immune-regulatory effects of TSLP on myeloid cells within the intestinal microenvironment suggest the contrary. Our objective was to clarify TSLP's role in sepsis. Cecal ligation and puncture was performed in mice with total or myeloid-specific deficiency in the TSLP receptor (TSLPR). Survival was monitored closely, peritoneal fluids and plasma were analyzed for markers of inflammation, and myeloid cell numbers and their ability to produce inflammatory mediators was determined. The interaction of TSLP with TSLPR in myeloid cells contributed to mouse survival after septic peritonitis. Mice with TSLPR deficiency in myeloid cells displayed excessive local and systemic inflammation levels (e.g., increased inflammatory cell and cytokine levels) relative to control mice. Moreover, hepatic injury was exacerbated in mice with TSLPR deficiency in their myeloid cells. However, the enhanced inflammatory response did not affect the ability of these mice to clear bacteria. Resident neutrophils and macrophages from septic mice with TSLPR deficiency exhibited an increased ability to produce proinflammatory cytokines. Collectively, our findings suggest that the effects of TSLP on myeloid cells are crucial in reducing the multiple organ failure that is associated with systemic inflammation, which highlights the significance of this cytokine in modulating the host response to infection and in reducing the risks of sepsis development.
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Thymic Stromal Lymphopoietin mediated epicutaneous inflammation promotes acute diarrhea and anaphylaxis
Journal of Clinical Investigation, 2014Co-Authors: Hongwei Han, Michael R. Comeau, Tennille D Thelen, Steven F. ZieglerAbstract:Atopic dermatitis (AD) and food allergy are closely linked; however, the mechanisms that guide the progression of AD to allergic inflammatory responses at other mucosal surfaces, including the gastrointestinal tract, are not well understood. Here, we determined that exposure of mice that have been epicutaneously sensitized with Thymic Stromal Lymphopoietin (TSLP) and antigen to repeated oral doses of the same antigen induced acute diarrhea and anaphylaxis. In this model, loss of TSLP signaling specifically in DCs led to loss of induced allergic diarrhea through lack of sensitization. While TSLP responses were not required during oral allergen challenge, CD4+ T cells were required and transferred disease when introduced into naive hosts. In addition, oral exposure to the antigen prior to skin sensitization blocked development of allergic disease. Finally, mice lacking the receptor for IL-25 failed to develop acute diarrhea and anaphylaxis, highlighting a role for IL-25 in the initiation of type 2 immunity in the intestine. These results demonstrate a role for TSLP and IL-25 in the atopic march from skin sensitization to food allergic responses and provide a model system for the generation of potential therapeutic interventions.
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IL-33 and Thymic Stromal Lymphopoietin Mediate Immune Pathology in Response to Chronic Airborne Allergen Exposure
Journal of immunology (Baltimore Md. : 1950), 2014Co-Authors: Steven F. Ziegler, Koji Iijima, Takao Kobayashi, Kenichiro Hara, Gail M. Kephart, Andrew N. J. Mckenzie, Hirohito KitaAbstract:Humans are frequently exposed to various airborne allergens in the atmospheric environment. These allergens may trigger a complex network of immune responses in the airways, resulting in asthma and other chronic airway diseases. In this study, we investigated the immunological mechanisms involved in the pathological changes induced by chronic exposure to multiple airborne allergens. Naive mice were exposed intranasally to a combination of common airborne allergens, including the house dust mite, Alternaria , and Aspergillus , for up to 8 wk. These allergens acted synergistically and induced robust eosinophilic airway inflammation, specific IgE Ab production, type 2 cytokine response, and airway hyperresponsiveness in 4 wk, followed by airway remodeling in 8 wk. Increased lung infiltration of T cells, B cells, and type 2 innate lymphoid cells was observed. CD4 + T cells and type 2 innate lymphoid cells contributed to the sources of IL-5 and IL-13, suggesting involvement of both innate and adaptive immunity in this model. The lung levels of IL-33 increased quickly within several hours after allergen exposure and continued to rise throughout the chronic phase of inflammation. Mice deficient in IL-33R ( Il1rl1 −/− ) and Thymic Stromal Lymphopoietin receptor ( Tslpr −/− ) showed significant reduction in airway inflammation, IgE Ab levels, and airway hyperresponsiveness. In contrast, mice deficient in IL-25R or IL-1R showed minimal differences as compared with wild-type animals. Thus, chronic exposure to natural airborne allergens triggers a network of innate and adaptive type 2 immune responses and airway pathology, and IL-33 and Thymic Stromal Lymphopoietin most likely play key roles in this process.
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increased density of intraepithelial mast cells in patients with exercise induced bronchoconstriction regulated through epithelially derived Thymic Stromal Lymphopoietin and il 33
The Journal of Allergy and Clinical Immunology, 2014Co-Authors: Ying Lai, Steven F. Ziegler, William A Altemeier, John Vandree, Adrian M Piliponsky, Brian Johnson, Cara L Appel, Charles W Frevert, Dallas M Hyde, Dirk E SmithAbstract:Background Exercise-induced bronchoconstriction (EIB) is a prototypical feature of indirect airway hyperresponsiveness. Mast cells are implicated in EIB, but the characteristics, regulation, and function of mast cells in patients with EIB are poorly understood. Objectives We sought to examine mast cell infiltration of the airway epithelium in patients with EIB and the regulation of mast cell phenotype and function by epithelially derived cytokines. Methods Endobronchial biopsy specimens, epithelial brushings, and induced sputum were obtained from asthmatic patients with and without EIB and healthy control subjects. Mast cell proteases were quantified by using quantitative PCR, and mast cell density was quantified by using design-based stereology. Airway epithelial responses to wounding and osmotic stress were assessed in primary airway epithelial cells and ex vivo murine lung tissue. Mast cell granule development and function were examined in cord blood–derived mast cells. Results Tryptase and carboxypeptidase A3 expression in epithelial brushings and epithelial mast cell density were selectively increased in the asthma group with EIB. An in vitro scratch wound initiated the release of Thymic Stromal Lymphopoietin, which was greater in epithelial cells derived from asthmatic patients. Osmotic stress induced the release of IL-33 from explanted murine lungs, which was increased in allergen-treated mice. Thymic Stromal Lymphopoietin combined with IL-33 increased tryptase and carboxypeptidase A3 immunostaining in mast cell precursors and selectively increased cysteinyl leukotriene formation by mast cells in a manner that was independent of in vitro sensitization. Conclusions Mast cell infiltration of the epithelium is a critical determinant of indirect airway hyperresponsiveness, and the airway epithelium might serve as an important regulator of the development and function of this mast cell population.
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cutting edge identification of the Thymic Stromal Lymphopoietin responsive dendritic cell subset critical for initiation of type 2 contact hypersensitivity
Journal of Immunology, 2013Co-Authors: Masayuki Kitajima, Steven F. ZieglerAbstract:The cytokine Thymic Stromal Lymphopoietin (TSLP) has been implicated in the initiation and progression of allergic inflammation through its ability to activate dendritic cells (DCs). However, the identity of the DC subset that responds to TSLP is not known. In this study we use a CCL17 reporter strain to identify the TSLP-responsive DC subset. In vitro, TSLP induced CD11b high DCs to express CCL17, to increase CCR7-mediated migration activity, and to drive Th2 differentiation of naive CD4 T cells. In vivo, following skin sensitization, we found that a subset of Ag-bearing CCL17 + CD11b high migratory DCs, but not Ag-bearing CCL17 − migratory DCs, in skin lymph nodes were capable of driving Th2 differentiation and were dramatically reduced in TSLPR-deficient mice. Taken together, these results demonstrate that TSLP activated a subset of CD11b + DCs in the skin to produce CCL17, upregulate CCR7, and migrate to the draining lymph node to initiate Th2 differentiation.
Michael R. Comeau - One of the best experts on this subject based on the ideXlab platform.
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Thymic Stromal Lymphopoietin mediated epicutaneous inflammation promotes acute diarrhea and anaphylaxis
Journal of Clinical Investigation, 2014Co-Authors: Hongwei Han, Michael R. Comeau, Tennille D Thelen, Steven F. ZieglerAbstract:Atopic dermatitis (AD) and food allergy are closely linked; however, the mechanisms that guide the progression of AD to allergic inflammatory responses at other mucosal surfaces, including the gastrointestinal tract, are not well understood. Here, we determined that exposure of mice that have been epicutaneously sensitized with Thymic Stromal Lymphopoietin (TSLP) and antigen to repeated oral doses of the same antigen induced acute diarrhea and anaphylaxis. In this model, loss of TSLP signaling specifically in DCs led to loss of induced allergic diarrhea through lack of sensitization. While TSLP responses were not required during oral allergen challenge, CD4+ T cells were required and transferred disease when introduced into naive hosts. In addition, oral exposure to the antigen prior to skin sensitization blocked development of allergic disease. Finally, mice lacking the receptor for IL-25 failed to develop acute diarrhea and anaphylaxis, highlighting a role for IL-25 in the initiation of type 2 immunity in the intestine. These results demonstrate a role for TSLP and IL-25 in the atopic march from skin sensitization to food allergic responses and provide a model system for the generation of potential therapeutic interventions.
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Thymic Stromal Lymphopoietin mediated extramedullary hematopoiesis promotes allergic inflammation inc5p 328
Journal of Immunology, 2014Co-Authors: Mark C Siracusa, Michael R. Comeau, Steven A. Saenz, Lisa C. Osborne, Kathryn Ruymann, Elia Tait D Wojno, Brain Kim, Hakon Hakonarson, Jonathan M Spergel, David ArtisAbstract:Extramedullary hematopoiesis (EMH) refers to the differentiation of hematopoietic stem cells (HSCs) into effector cells that occurs in compartments outside of the bone marrow. Previous studies linked pattern recognition receptor (PRR)-expressing HSCs, EMH and immune responses to microbial stimuli. However, whether EMH operates in broader immune contexts remains unknown. Here, we demonstrate a previously unrecognized role for Thymic Stromal Lymphopoietin (TSLP) in promoting the population expansion of progenitor cells in the periphery and identify that TSLP-elicited progenitors differentiated into effector cells including macrophages and granulocytes; and that these cells selectively contributed to type 2 cytokine responses. The frequency of circulating progenitor cells was also increased in allergic patients with a gain-of-function polymorphism in TSLP, suggesting the TSLP-EMH pathway may operate in human disease. These data demonstrate that TSLP-induced EMH contributes to the development of Th2 cytokine-mediated inflammation and indicate that EMH is a conserved mechanism of innate immunity.
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Thymic Stromal Lymphopoietin amplifies the differentiation of alternatively activated macrophages
Journal of Immunology, 2013Co-Authors: Hongwei Han, Michael R. Comeau, Steven F. Ziegler, Baohua Zhou, Mark B HeadleyAbstract:The epithelial-derived cytokine Thymic Stromal Lymphopoietin (TSLP) has been associated with the promotion of type 2 inflammation and the induction of allergic disease. In humans TSLP is elevated in the lungs of asthma patients and in the lesional skin of individuals with atopic dermatitis, whereas mice lacking TSLP responses are refractory to models of Th2-driven allergic disease. Although several cell types, including dendritic cells, basophils, and CD4 T cells, have been shown to respond to TSLP, its role in macrophage differentiation has not been studied. Type 2 cytokines (i.e., IL-4 and IL-13) can drive the differentiation of macrophages into alternatively activated macrophages (aaMϕs, also referred to as M2 macrophages). This population of macrophages is associated with allergic inflammation. We therefore reasoned that TSLP/TSLPR signaling may be involved in the differentiation and activation of aaMϕs during allergic airway inflammation. In this study, we report that TSLP changes the quiescent phenotype of pulmonary macrophages toward an aaMϕ phenotype during TSLP-induced airway inflammation. This differentiation of airway macrophages was IL-13–, but not IL-4–, dependent. Taken together, we demonstrate in this study that TSLP/TSLPR plays a significant role in the amplification of aaMΦ polarization and chemokine production, thereby contributing to 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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Thymic Stromal Lymphopoietin tslp mediated dermal inflammation aggravates experimental asthma
Mucosal Immunology, 2012Co-Authors: Hongwei Han, Michael R. Comeau, Steven F. Ziegler, Miyuki Omori, Mark B Headley, Heidi K Jessup, Karen S Lee, Ann MarshakrothsteinAbstract:Individuals with one atopic disease are far more likely to develop a second. Approximately half of all atopic dermatitis (AD) patients subsequently develop asthma, particularly those with severe AD. This association, suggesting a role for AD as an entry point for subsequent allergic disease, is a phenomenon known as the "atopic march." Although the underlying cause of the atopic march remains unknown, recent evidence suggests a role for the cytokine Thymic Stromal Lymphopoietin (TSLP). We have established a mouse model to determine whether TSLP plays a role in this phenomenon, and in this study show that mice exposed to the antigen ovalbumin (OVA) in the skin in the presence of TSLP develop severe airway inflammation when later challenged with the same antigen in the lung. Interestingly, neither TSLP production in the lung nor circulating TSLP is required to aggravate the asthma that was induced upon subsequent antigen challenge. However, CD4 T cells are required in the challenge phase of the response, as was challenge with the sensitizing antigen, demonstrating that the response was antigen specific. This study, which provides a clean mouse model to study human atopic march, indicates that skin-derived TSLP may represent an important factor that triggers progression from AD to asthma.
Mark C Siracusa - One of the best experts on this subject based on the ideXlab platform.
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Thymic Stromal Lymphopoietin mediated extramedullary hematopoiesis promotes allergic inflammation inc5p 328
Journal of Immunology, 2014Co-Authors: Mark C Siracusa, Michael R. Comeau, Steven A. Saenz, Lisa C. Osborne, Kathryn Ruymann, Elia Tait D Wojno, Brain Kim, Hakon Hakonarson, Jonathan M Spergel, David ArtisAbstract:Extramedullary hematopoiesis (EMH) refers to the differentiation of hematopoietic stem cells (HSCs) into effector cells that occurs in compartments outside of the bone marrow. Previous studies linked pattern recognition receptor (PRR)-expressing HSCs, EMH and immune responses to microbial stimuli. However, whether EMH operates in broader immune contexts remains unknown. Here, we demonstrate a previously unrecognized role for Thymic Stromal Lymphopoietin (TSLP) in promoting the population expansion of progenitor cells in the periphery and identify that TSLP-elicited progenitors differentiated into effector cells including macrophages and granulocytes; and that these cells selectively contributed to type 2 cytokine responses. The frequency of circulating progenitor cells was also increased in allergic patients with a gain-of-function polymorphism in TSLP, suggesting the TSLP-EMH pathway may operate in human disease. These data demonstrate that TSLP-induced EMH contributes to the development of Th2 cytokine-mediated inflammation and indicate that EMH is a conserved mechanism of innate immunity.
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Thymic Stromal Lymphopoietin-Mediated Extramedullary Hematopoiesis Promotes Allergic Inflammation
Immunity, 2013Co-Authors: Mark C Siracusa, Steven A. Saenz, Elia D. Tait Wojno, Brian S. Kim, Lisa C. Osborne, Carly G. K. Ziegler, Alain Benitez, Kathryn Ruymann, Donna L. Farber, Patrick M.a. SleimanAbstract:Extramedullary hematopoiesis (EMH) refers to the differentiation of hematopoietic stem cells (HSCs) into effector cells that occurs in compartments outside of the bone marrow. Previous studies linked pattern-recognition receptor (PRR)-expressing HSCs, EMH, and immune responses to microbial stimuli. However, whether EMH operates in broader immune contexts remains unknown. Here, we demonstrate a previously unrecognized role for Thymic Stromal Lymphopoietin (TSLP) in promoting the population expansion of progenitor cells in the periphery and identify that TSLP-elicited progenitors differentiated into effector cells including macrophages, dendritic cells, and granulocytes and that these cells contributed to type 2 cytokine responses. The frequency of circulating progenitor cells was also increased in allergic patients with a gain-of-function polymorphism in TSLP, suggesting the TSLP-EMH pathway might operate in human disease. These data identify that TSLP-induced EMH contributes to the development of allergic inflammation and indicate that EMH is a conserved mechanism of innate immunity.
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Thymic Stromal Lymphopoietin elicited basophil responses promote eosinophilic esophagitis
Nature Medicine, 2013Co-Authors: Mark C Siracusa, Paul R Giacomin, Brian S. Kim, Alain Benitez, Kathryn Ruymann, Mario Noti, Elia Tait D Wojno, Meera G NairAbstract:Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes Thymic Stromal Lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.
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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.
Yongjun Liu - One of the best experts on this subject based on the ideXlab platform.
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il 13 induces skin fibrosis in atopic dermatitis by Thymic Stromal Lymphopoietin
Journal of Immunology, 2011Co-Authors: Allen C Myers, Warren J Leonard, Yongjun Liu, Zhou Zhu, Tao ZhengAbstract:Skin fibrotic remodeling is a major feature in human atopic dermatitis (AD). Inflammation and tissue fibrosis are common consequences of Th2 responses. Elevated IL-13 and Thymic Stromal Lymphopoietin (TSLP) have been found in the AD skin lesions. Fibrocytes can be recruited to inflamed tissues to promote wound healing and fibrosis. Dermal transgenic expression of IL-13 causes an AD-like phenotype with fibrosis and increased TSLP. However, the role of TSLP in fibrotic remodeling is unknown. In this study, we investigated the role of TSLP and fibrocytes in the generation of IL-13-induced skin fibrosis. In AD lesion, cessation of IL-13 transgene expression resulted in reduced skin inflammation but with no effect on further progression of fibrosis. This was accompanied by markedly increased CD34(+)/procollagen 1(+) fibrocytes. Furthermore, fibrocytes express TSLP receptor (TSLPR), and TSLP directly promotes PBMC-derived fibrocytes to produce collagen. Neutralization of TSLP or genetic deletion of TSLPR in IL-13 transgenic mice resulted in a significant reduction in fibrocytes and in skin fibrosis. Furthermore, reduction of fibrosis by depletion of TSLP was independent of IL-13. Interestingly, the number of fibrocytes was highly increased in the skin samples of AD patients. These data indicate that the progression of skin fibrosis in IL-13-induced AD occurs via TSLP/TSLPR-dependent but IL-13-independent novel mechanisms by promoting fibrocyte functions.
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early production of Thymic Stromal Lymphopoietin precedes infiltration of dendritic cells expressing its receptor in allergen induced late phase cutaneous responses in atopic subjects
Allergy, 2009Co-Authors: C J Corrigan, Yongjun Liu, Yuihsi Wang, A Jayaratnam, R De Waal Malefyt, Qiu Meng, A B Kay, Simon Phipps, T H Lee, Sun YingAbstract:Thymic Stromal Lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine that triggers dendritic cell-mediated T helper (Th)2 inflammatory responses through a receptor consisting of a heterodimer of the IL-7 receptor alpha (IL-7R alpha) chain and the TSLP receptor (TSLPR), which resembles the cytokine receptor common gamma chain. Dendritic cells activated by TSLP prime development of CD4(+) T cells into Th2 cells contributing to the pathogenesis of allergic inflammation. We hypothesized that allergen exposure induces expression of TSLP and results in recruitment of TSLPR bearing cells in the cutaneous allergen-induced late-phase reaction (LPR) in atopic subjects.
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Thymic Stromal Lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses.
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2009Co-Authors: Yuihsi Wang, Yongjun LiuAbstract:Allergic diseases are often triggered by environmental allergens that induce dominant type 2 immune responses, characterized by the infiltrated T-helper type 2 (TH2) lymphocytes, eosinophils, and elevated TH2 cytokines. In addition to TH2 type immune responses, epithelial stress and injury linked to tissue remodelling are often observed, suggesting that epithelial cells may play important role in regulating allergic responses. Dendritic cells (DCs), the professional antigen-presenting cells with the capabilities of sampling allergens, are considered as the key player on instructing TH2 immune responses. Whether inflamed epithelium can regulate innate immunity, such as macrophages and DCs, which in turn instructs adaptive immunity has long been hypothesized. Studies of Thymic Stromal Lymphopoietin (TSLP), an epithelial cells-derived cytokine, that can strongly activate DCs, provide important evidences that the epithelial barrier can trigger allergic diseases by regulating immune responses. The finding that OX40/OX40Ligand (OX40L) interactions are the molecular trigger responsible for the induction and maintenance of TH2 responses by TSLP-activated DCs provides a plausible molecular explanation for TSLP-mediated allergy. Recent progresses in characterizing the pro-inflammatory IL-17 cytokine family have added an additional layer of complexity on the regulation of allergic inflammation. TSLP-DCs can induce a robust expansion of TH2 memory cells and strengthen functional attributes by up-regulating their surface expression of IL-17RB (IL-25R), the receptor for cytokine IL-17E (IL-25), a distinct member of IL-17 cytokine family. IL-17E (also known as IL-25) produced by epithelial cells, and other innate cells, such as eosinphils, basophils, and mast cells, are shown to regulate adaptive immunity by enhancing TH2 cytokine productions. These exciting findings expand our knowledge of the complex immunological cascades that result in allergic inflammation and may provide novel therapeutic approaches for the treatment of allergic diseases.
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Thymic Stromal Lymphopoietin and ox40 ligand pathway in the initiation of dendritic cell mediated allergic inflammation
The Journal of Allergy and Clinical Immunology, 2007Co-Authors: Yongjun LiuAbstract:It was demonstrated 5 years ago that Thymic Stromal Lymphopoietin (TSLP), a IL-7–like cytokine produced by epithelial cells, could strongly activate human myeloid dendritic cells to induce an inflammatory TH2 response characterized by high TNF-α and little IL-10 production, distinct from the regulatory TH2 responses characterized by low TNF-α and high IL-10 production. TSLP was found highly expressed by keratinocytes of skin lesions of atopic dermatitis and associated with dendritic cell activation in situ. This suggests for the first time that TSLP represents a master switch of allergic inflammation at the epithelial cell and dendritic cell interface. During the last several years, the evidence for the association of TSLP with human asthma was revealed. The direct link between TSLP expression with the pathogenesis of atopic dermatitis and asthma in vivo was demonstrated. In addition, OX40 ligand was found to be the TSLP-induced molecule on dendritic cells that triggers inflammatory TH2 differentiation in the absence of IL-12. TSLP was also demonstrated to direct the innate phase of allergic immune responses through activating mast cells. Therefore, TSLP and OX40 ligand may represent important targets for intervention of the initiation of allergic inflammatory responses.
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cutting edge direct action of Thymic Stromal Lymphopoietin on activated human cd4 t cells
Journal of Immunology, 2007Co-Authors: Irina Rochman, Norihiko Watanabe, Yongjun Liu, Kazuhiko Arima, Warren J LeonardAbstract:Thymic Stromal Lymphopoietin (TSLP) is a cytokine that promotes CD4 + T cell homeostasis and contributes to allergic and inflammatory responses. TSLP can act directly on mouse CD4 + T cells, but in humans, the available data have indicated that TSLP receptors are not expressed on CD4 + T cells and that TSLP instead activates dendritic cells, which in turn promote the proliferation and differentiation of CD4 + T cells. We now unexpectedly demonstrate the presence of TSLP receptors on activated human CD4 + T cells. Strikingly, whereas freshly isolated peripheral blood human T cells show little if any response to TSLP, TCR stimulation allows a potent response to this cytokine. Moreover, TSLP increases the sensitivity of human CD4 + T cells to low doses of IL-2, augmenting responsiveness of these cells to TCR engagement. Our results establish that human CD4 + T cells are direct targets for TSLP.
Patrick M.a. Sleiman - One of the best experts on this subject based on the ideXlab platform.
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Thymic Stromal Lymphopoietin-Mediated Extramedullary Hematopoiesis Promotes Allergic Inflammation
Immunity, 2013Co-Authors: Mark C Siracusa, Steven A. Saenz, Elia D. Tait Wojno, Brian S. Kim, Lisa C. Osborne, Carly G. K. Ziegler, Alain Benitez, Kathryn Ruymann, Donna L. Farber, Patrick M.a. SleimanAbstract:Extramedullary hematopoiesis (EMH) refers to the differentiation of hematopoietic stem cells (HSCs) into effector cells that occurs in compartments outside of the bone marrow. Previous studies linked pattern-recognition receptor (PRR)-expressing HSCs, EMH, and immune responses to microbial stimuli. However, whether EMH operates in broader immune contexts remains unknown. Here, we demonstrate a previously unrecognized role for Thymic Stromal Lymphopoietin (TSLP) in promoting the population expansion of progenitor cells in the periphery and identify that TSLP-elicited progenitors differentiated into effector cells including macrophages, dendritic cells, and granulocytes and that these cells contributed to type 2 cytokine responses. The frequency of circulating progenitor cells was also increased in allergic patients with a gain-of-function polymorphism in TSLP, suggesting the TSLP-EMH pathway might operate in human disease. These data identify that TSLP-induced EMH contributes to the development of allergic inflammation and indicate that EMH is a conserved mechanism of innate immunity.
