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Rafeul Alam - One of the best experts on this subject based on the ideXlab platform.
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Experimental Asthma persists in il 33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin driven il 9 and il 13 type 2 innate lymphoid cell subpopulations
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Mukesh Verma, Magdalena M. Gorska, Sucai Liu, Lidia Michalec, Anand Sripada, Rafeul AlamAbstract:Background IL-33 plays an important role in the development of Experimental Asthma. Objective We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of Asthma in a mouse model. Methods We studied allergen-induced Experimental Asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry. Results Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of Experimental Asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13 + CD4 T cells, forkhead box P3–positive regulatory T cells, and IL-5 + ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45 + lin − CD25 + cells) and IL-13 + ILC2s, emergence of a TSLP receptor–positive IL-9 + ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9 + and IL-13 + ILC2 numbers in the lung. Conclusions Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9 + and IL-13 + ILC2s and mast cells and leads to development of chronic Experimental Asthma. An anti-TSLP antibody abrogates all pathologic features of Asthma in this model.
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Experimental Asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin–driven IL-9+ and IL-13+ type 2 innate lymphoid cell subpopulations
The Journal of allergy and clinical immunology, 2017Co-Authors: Mukesh Verma, Magdalena M. Gorska, Sucai Liu, Lidia Michalec, Anand Sripada, Rafeul AlamAbstract:Background IL-33 plays an important role in the development of Experimental Asthma. Objective We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of Asthma in a mouse model. Methods We studied allergen-induced Experimental Asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry. Results Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of Experimental Asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13 + CD4 T cells, forkhead box P3–positive regulatory T cells, and IL-5 + ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45 + lin − CD25 + cells) and IL-13 + ILC2s, emergence of a TSLP receptor–positive IL-9 + ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9 + and IL-13 + ILC2 numbers in the lung. Conclusions Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9 + and IL-13 + ILC2s and mast cells and leads to development of chronic Experimental Asthma. An anti-TSLP antibody abrogates all pathologic features of Asthma in this model.
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ERK1 is important for Th2 differentiation and development of Experimental Asthma
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2012Co-Authors: Nick P. Goplen, Zunayet Karim, Lei Guo, Yonghua Zhuang, Hua Huang, Magdalena M. Gorska, Erwin W. Gelfand, Gilles Pagès, Jacques Pouysségur, Rafeul AlamAbstract:The ERK1/2 signaling pathway regulates a variety of T-cell functions. We observed dynamic changes in the expression of ERK1/2 during T-helper cell differentiation. Specifically, the expression of ERK1/2 was decreased and increased by IL-12 and IL-4, respectively. To address this subject further, we examined the specific role of ERK1 in Th2 differentiation and development of Experimental Asthma using ERK1(-/-) mice. ERK1(-/-) mice were unable to mount airway inflammation and hyperreactivity in two different models of Asthma, acute and chronic. ERK1(-/-) mice had reduced expression of Th2 cytokines IL-4 and IL-5 but not IL-17A or IFN-γ. They had reduced levels of allergen-specific IgE and blood eosinophils. T cells from immunized ERK1(-/-) mice manifested reduced proliferation in response to the sensitizing allergen. ERK1(-/-) T cells had reduced and short-lived expression of JunB following TCR stimulation, which likely contributed to their impaired Th2 differentiation. Immunized ERK1(-/-) mice showed reduced numbers of CD44(high) CD4 T cells in the spleen. In vitro studies demonstrated that Th2 but not Th1 cells from ERK1(-/-) mice had reduced numbers of CD44(high) cells. Finally, CD4 T cells form ERK1(-/-) mice expressed higher levels of BIM under growth factor-deprived conditions and reduced Mcl-1 on stimulation. As a result, the survival of CD4 T cells, especially CD44(high) Th2 cells, was much reduced in ERK1(-/-) mice. We conclude that ERK1 plays a nonredundant role in Th2 differentiation and development of Experimental Asthma. ERK1 controls Th2 differentiation and survival through its effect on JunB and BIM, respectively.
Mukesh Verma - One of the best experts on this subject based on the ideXlab platform.
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Experimental Asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin–driven IL-9+ and IL-13+ type 2 innate lymphoid cell subpopulations
The Journal of allergy and clinical immunology, 2017Co-Authors: Mukesh Verma, Magdalena M. Gorska, Sucai Liu, Lidia Michalec, Anand Sripada, Rafeul AlamAbstract:Background IL-33 plays an important role in the development of Experimental Asthma. Objective We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of Asthma in a mouse model. Methods We studied allergen-induced Experimental Asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry. Results Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of Experimental Asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13 + CD4 T cells, forkhead box P3–positive regulatory T cells, and IL-5 + ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45 + lin − CD25 + cells) and IL-13 + ILC2s, emergence of a TSLP receptor–positive IL-9 + ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9 + and IL-13 + ILC2 numbers in the lung. Conclusions Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9 + and IL-13 + ILC2s and mast cells and leads to development of chronic Experimental Asthma. An anti-TSLP antibody abrogates all pathologic features of Asthma in this model.
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Experimental Asthma persists in il 33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin driven il 9 and il 13 type 2 innate lymphoid cell subpopulations
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Mukesh Verma, Magdalena M. Gorska, Sucai Liu, Lidia Michalec, Anand Sripada, Rafeul AlamAbstract:Background IL-33 plays an important role in the development of Experimental Asthma. Objective We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of Asthma in a mouse model. Methods We studied allergen-induced Experimental Asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry. Results Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of Experimental Asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13 + CD4 T cells, forkhead box P3–positive regulatory T cells, and IL-5 + ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45 + lin − CD25 + cells) and IL-13 + ILC2s, emergence of a TSLP receptor–positive IL-9 + ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9 + and IL-13 + ILC2 numbers in the lung. Conclusions Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9 + and IL-13 + ILC2s and mast cells and leads to development of chronic Experimental Asthma. An anti-TSLP antibody abrogates all pathologic features of Asthma in this model.
Magdalena M. Gorska - One of the best experts on this subject based on the ideXlab platform.
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Experimental Asthma persists in il 33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin driven il 9 and il 13 type 2 innate lymphoid cell subpopulations
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Mukesh Verma, Magdalena M. Gorska, Sucai Liu, Lidia Michalec, Anand Sripada, Rafeul AlamAbstract:Background IL-33 plays an important role in the development of Experimental Asthma. Objective We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of Asthma in a mouse model. Methods We studied allergen-induced Experimental Asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry. Results Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of Experimental Asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13 + CD4 T cells, forkhead box P3–positive regulatory T cells, and IL-5 + ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45 + lin − CD25 + cells) and IL-13 + ILC2s, emergence of a TSLP receptor–positive IL-9 + ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9 + and IL-13 + ILC2 numbers in the lung. Conclusions Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9 + and IL-13 + ILC2s and mast cells and leads to development of chronic Experimental Asthma. An anti-TSLP antibody abrogates all pathologic features of Asthma in this model.
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Experimental Asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin–driven IL-9+ and IL-13+ type 2 innate lymphoid cell subpopulations
The Journal of allergy and clinical immunology, 2017Co-Authors: Mukesh Verma, Magdalena M. Gorska, Sucai Liu, Lidia Michalec, Anand Sripada, Rafeul AlamAbstract:Background IL-33 plays an important role in the development of Experimental Asthma. Objective We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of Asthma in a mouse model. Methods We studied allergen-induced Experimental Asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry. Results Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of Experimental Asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13 + CD4 T cells, forkhead box P3–positive regulatory T cells, and IL-5 + ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45 + lin − CD25 + cells) and IL-13 + ILC2s, emergence of a TSLP receptor–positive IL-9 + ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9 + and IL-13 + ILC2 numbers in the lung. Conclusions Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9 + and IL-13 + ILC2s and mast cells and leads to development of chronic Experimental Asthma. An anti-TSLP antibody abrogates all pathologic features of Asthma in this model.
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ERK1 is important for Th2 differentiation and development of Experimental Asthma
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2012Co-Authors: Nick P. Goplen, Zunayet Karim, Lei Guo, Yonghua Zhuang, Hua Huang, Magdalena M. Gorska, Erwin W. Gelfand, Gilles Pagès, Jacques Pouysségur, Rafeul AlamAbstract:The ERK1/2 signaling pathway regulates a variety of T-cell functions. We observed dynamic changes in the expression of ERK1/2 during T-helper cell differentiation. Specifically, the expression of ERK1/2 was decreased and increased by IL-12 and IL-4, respectively. To address this subject further, we examined the specific role of ERK1 in Th2 differentiation and development of Experimental Asthma using ERK1(-/-) mice. ERK1(-/-) mice were unable to mount airway inflammation and hyperreactivity in two different models of Asthma, acute and chronic. ERK1(-/-) mice had reduced expression of Th2 cytokines IL-4 and IL-5 but not IL-17A or IFN-γ. They had reduced levels of allergen-specific IgE and blood eosinophils. T cells from immunized ERK1(-/-) mice manifested reduced proliferation in response to the sensitizing allergen. ERK1(-/-) T cells had reduced and short-lived expression of JunB following TCR stimulation, which likely contributed to their impaired Th2 differentiation. Immunized ERK1(-/-) mice showed reduced numbers of CD44(high) CD4 T cells in the spleen. In vitro studies demonstrated that Th2 but not Th1 cells from ERK1(-/-) mice had reduced numbers of CD44(high) cells. Finally, CD4 T cells form ERK1(-/-) mice expressed higher levels of BIM under growth factor-deprived conditions and reduced Mcl-1 on stimulation. As a result, the survival of CD4 T cells, especially CD44(high) Th2 cells, was much reduced in ERK1(-/-) mice. We conclude that ERK1 plays a nonredundant role in Th2 differentiation and development of Experimental Asthma. ERK1 controls Th2 differentiation and survival through its effect on JunB and BIM, respectively.
Anand Sripada - One of the best experts on this subject based on the ideXlab platform.
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Experimental Asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin–driven IL-9+ and IL-13+ type 2 innate lymphoid cell subpopulations
The Journal of allergy and clinical immunology, 2017Co-Authors: Mukesh Verma, Magdalena M. Gorska, Sucai Liu, Lidia Michalec, Anand Sripada, Rafeul AlamAbstract:Background IL-33 plays an important role in the development of Experimental Asthma. Objective We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of Asthma in a mouse model. Methods We studied allergen-induced Experimental Asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry. Results Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of Experimental Asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13 + CD4 T cells, forkhead box P3–positive regulatory T cells, and IL-5 + ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45 + lin − CD25 + cells) and IL-13 + ILC2s, emergence of a TSLP receptor–positive IL-9 + ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9 + and IL-13 + ILC2 numbers in the lung. Conclusions Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9 + and IL-13 + ILC2s and mast cells and leads to development of chronic Experimental Asthma. An anti-TSLP antibody abrogates all pathologic features of Asthma in this model.
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Experimental Asthma persists in il 33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin driven il 9 and il 13 type 2 innate lymphoid cell subpopulations
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Mukesh Verma, Magdalena M. Gorska, Sucai Liu, Lidia Michalec, Anand Sripada, Rafeul AlamAbstract:Background IL-33 plays an important role in the development of Experimental Asthma. Objective We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of Asthma in a mouse model. Methods We studied allergen-induced Experimental Asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry. Results Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of Experimental Asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13 + CD4 T cells, forkhead box P3–positive regulatory T cells, and IL-5 + ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45 + lin − CD25 + cells) and IL-13 + ILC2s, emergence of a TSLP receptor–positive IL-9 + ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9 + and IL-13 + ILC2 numbers in the lung. Conclusions Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9 + and IL-13 + ILC2s and mast cells and leads to development of chronic Experimental Asthma. An anti-TSLP antibody abrogates all pathologic features of Asthma in this model.
Lidia Michalec - One of the best experts on this subject based on the ideXlab platform.
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Experimental Asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin–driven IL-9+ and IL-13+ type 2 innate lymphoid cell subpopulations
The Journal of allergy and clinical immunology, 2017Co-Authors: Mukesh Verma, Magdalena M. Gorska, Sucai Liu, Lidia Michalec, Anand Sripada, Rafeul AlamAbstract:Background IL-33 plays an important role in the development of Experimental Asthma. Objective We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of Asthma in a mouse model. Methods We studied allergen-induced Experimental Asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry. Results Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of Experimental Asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13 + CD4 T cells, forkhead box P3–positive regulatory T cells, and IL-5 + ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45 + lin − CD25 + cells) and IL-13 + ILC2s, emergence of a TSLP receptor–positive IL-9 + ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9 + and IL-13 + ILC2 numbers in the lung. Conclusions Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9 + and IL-13 + ILC2s and mast cells and leads to development of chronic Experimental Asthma. An anti-TSLP antibody abrogates all pathologic features of Asthma in this model.
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Experimental Asthma persists in il 33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin driven il 9 and il 13 type 2 innate lymphoid cell subpopulations
The Journal of Allergy and Clinical Immunology, 2017Co-Authors: Mukesh Verma, Magdalena M. Gorska, Sucai Liu, Lidia Michalec, Anand Sripada, Rafeul AlamAbstract:Background IL-33 plays an important role in the development of Experimental Asthma. Objective We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of Asthma in a mouse model. Methods We studied allergen-induced Experimental Asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry. Results Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of Experimental Asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13 + CD4 T cells, forkhead box P3–positive regulatory T cells, and IL-5 + ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45 + lin − CD25 + cells) and IL-13 + ILC2s, emergence of a TSLP receptor–positive IL-9 + ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9 + and IL-13 + ILC2 numbers in the lung. Conclusions Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9 + and IL-13 + ILC2s and mast cells and leads to development of chronic Experimental Asthma. An anti-TSLP antibody abrogates all pathologic features of Asthma in this model.
