Deficiency of PI3-Kinase catalytic isoforms p110γ and p110δ in mice enhances the IL-17/G-CSF axis and induces neutrophilia
| Autor: | Fee Schmitt, Carolin Blumendeller, Roland P. Piekorz, Sandra Beer-Hammer, Kirsten Bucher, Bernd Nürnberg, Benedikt Mothes, Emilio Hirsch, Daniel Schäll |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Neutrophils medicine.medical_treatment Chemokine CXCL1 T-Lymphocytes Chemokine CXCL2 lcsh:Medicine Biochemistry Mice Phosphatidylinositol 3-Kinases IL-17-producing T cells Granulocyte Colony-Stimulating Factor Homeostasis Lung Cells Cultured Il-17 lcsh:Cytology Interleukin-17 PI3K p110δ CXCL1 Isoenzymes CXCL2 Cytokine medicine.anatomical_structure PI3K p110γ G-CSF PI3K p110δ neutrophil homeostasis neutrophil homeostasis Interleukin 17 medicine.symptom medicine.medical_specialty T cell Biology 03 medical and health sciences Internal medicine medicine Animals lcsh:QH573-671 Neutrophil homeostasis Molecular Biology Research lcsh:R Cell Biology Neutrophilia Mice Inbred C57BL 030104 developmental biology Endocrinology P110δ Leukocyte Disorders Spleen |
| Zdroj: | Cell Communication and Signaling : CCS Cell Communication and Signaling, Vol 15, Iss 1, Pp 1-15 (2017) |
| ISSN: | 1478-811X |
| Popis: | Background Phosphoinositide 3-kinase γ (PI3Kγ) and PI3Kδ are second messenger-generating enzymes with key roles in proliferation, differentiation, survival, and function of leukocytes. Deficiency of the catalytic subunits p110γ and p110δ of PI3Kγ and PI3Kδ in p110γ/δ−/− mice leads to defective B- and T-cell homeostasis. Here we examined the role of p110γ and p110δ in the homeostasis of neutrophils by analyzing p110γ−/−, p110δ−/− and p110γ/δ−/− mice. Methods Neutrophils and T cells in leukocyte suspensions from the bone marrow (BM), blood, spleen and lung were analyzed by flow cytometry. Serum concentrations of IL-17, of the neutrophilic growth factor G-CSF, and of the neutrophil mobilizing CXC chemokines CXCL1/KC and CXCL2/MIP-2 were measured by Bio-Plex assay. Production of G-CSF and CXCL1/KC by IL-17-stimulated primary lung tissue cells were determined by ELISA, whereas IL-17-dependent signaling in lung tissue cells was analyzed by measuring Akt phosphorylation using immunoblot. Results We found that in contrast to single knock-out mice, p110γ/δ−/− mice exhibited significantly elevated neutrophil counts in blood, spleen, and lung. Increased granulocytic differentiation stages in the bone marrow of p110γ/δ−/− mice were paralleled by increased serum concentrations of G-CSF, CXCL1/KC, and CXCL2/MIP-2. As IL-17 induces neutrophilia via the induction of G-CSF and CXC chemokines, we measured IL-17 and IL-17-producing T cells. IL-17 serum concentrations and frequencies of IL-17+ splenic T cells were significantly increased in p110γ/δ−/− mice. Moreover, IFN-γ+, IL-4+, and IL-5+ T cell subsets were drastically increased in p110γ/δ−/− mice, suggesting that IL-17+ T cells were up-regulated in the context of a general percentage increase of other cytokine producing T cell subsets. Conclusions We found that p110γ/δ deficiency in mice induces complex immunological changes, which might in concert contribute to neutrophilia. These findings emphasize a crucial but indirect role of both p110γ and p110δ in the regulation of neutrophil homeostasis. Electronic supplementary material The online version of this article (doi:10.1186/s12964-017-0185-y) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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