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SHIP-1 Regulation of Innate Immune Cells in the Generation of Allergic Inflammation
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A1270 - SHIP-1 Regulation of Innate Immune Cells in the Generation of Allergic Inflammation
Author Block: X. Ye1, Y. Wei1, F. Zhang1, L. Wang1, L. Zhang1, H. Tang1, Z. Chen1, W. G. Kerr2, T. Zheng1, Z. Zhu3; 1Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT, United States, 2Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, United States, 3Molecular Microbiology and Immunology, Brown Univ Med School, Providence, RI, United States.
Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP-1) controls the intracellular levels of the phosphoinositide 3-kinase (PI3K) product phosphotidylinositol-3, 4, 5-trisphosphate and functions as a negative regulator of cytokine and immune receptor signaling. Emerging evidence suggests that the PI3K pathway is involved in allergic inflammation in the lung. Germline or induced whole-body SHIP-1-deficient mice experience spontaneous type 2-dominated pulmonary inflammation, demonstrating that SHIP-1 is essential for lung homeostasis and is a negative regulator of lung inflammation. The mechanisms by which SHIP-1 regulates lung inflammation and the responsible cell types are still unclear. Deletion of SHIP-1 selectively in B cells, T cells, dendritic cells (DC) or macrophages did not lead to spontaneous allergic inflammation in mice. Instead, T cell-specific deletion of SHIP-1 has led to impaired Th2 immune response to helminth infection. These suggest that innate immune cells, particularly group 2 innate lymphoid cells (ILC2 cells) may play an important role in this process. We tested this idea using mice with deletion of SHIP-1 in the hematopoietic cell lineage. Conditional deletion of SHIP-1 in hematopoietic cells in Tek-Cre/SHIP-1 mice resulted in spontaneous pulmonary inflammation with features of Th2 immune response and airway remodeling similar to those seen in mice with global deletion of SHIP-1. Furthermore, compared with the wild type control mice, Tek-Cre/SHIP-1 mice displayed a dramatic increase in the number of IL-5/IL-13 producing ILC2 cells in the lung at baseline and after stimulation by allergen papain. These findings provide strong evidence that the PI3K pathway is involved in ILC2 cell development and SHIP-1 is required to restrain ILC2 cells and type 2 immunity in the lung.
Author Block: X. Ye1, Y. Wei1, F. Zhang1, L. Wang1, L. Zhang1, H. Tang1, Z. Chen1, W. G. Kerr2, T. Zheng1, Z. Zhu3; 1Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT, United States, 2Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, United States, 3Molecular Microbiology and Immunology, Brown Univ Med School, Providence, RI, United States.
Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP-1) controls the intracellular levels of the phosphoinositide 3-kinase (PI3K) product phosphotidylinositol-3, 4, 5-trisphosphate and functions as a negative regulator of cytokine and immune receptor signaling. Emerging evidence suggests that the PI3K pathway is involved in allergic inflammation in the lung. Germline or induced whole-body SHIP-1-deficient mice experience spontaneous type 2-dominated pulmonary inflammation, demonstrating that SHIP-1 is essential for lung homeostasis and is a negative regulator of lung inflammation. The mechanisms by which SHIP-1 regulates lung inflammation and the responsible cell types are still unclear. Deletion of SHIP-1 selectively in B cells, T cells, dendritic cells (DC) or macrophages did not lead to spontaneous allergic inflammation in mice. Instead, T cell-specific deletion of SHIP-1 has led to impaired Th2 immune response to helminth infection. These suggest that innate immune cells, particularly group 2 innate lymphoid cells (ILC2 cells) may play an important role in this process. We tested this idea using mice with deletion of SHIP-1 in the hematopoietic cell lineage. Conditional deletion of SHIP-1 in hematopoietic cells in Tek-Cre/SHIP-1 mice resulted in spontaneous pulmonary inflammation with features of Th2 immune response and airway remodeling similar to those seen in mice with global deletion of SHIP-1. Furthermore, compared with the wild type control mice, Tek-Cre/SHIP-1 mice displayed a dramatic increase in the number of IL-5/IL-13 producing ILC2 cells in the lung at baseline and after stimulation by allergen papain. These findings provide strong evidence that the PI3K pathway is involved in ILC2 cell development and SHIP-1 is required to restrain ILC2 cells and type 2 immunity in the lung.
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