Deficiency of PI3-Kinase catalytic isoforms p110γ and p110δ in mice enhances the IL-17/G-CSF axis and induces neutrophilia

• Published in: Cell communication and signaling Vol. 15; no. 1; p. 28
• Main Authors: Bucher, Kirsten, Schmitt, Fee, Mothes, Benedikt, Blumendeller, Carolin, Schäll, Daniel, Piekorz, Roland, Hirsch, Emilio, Nürnberg, Bernd, Beer-Hammer, Sandra
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 19-07-2017; BioMed Central; BMC
• Subjects: Analysis; Animals; Cells, Cultured; Chemokine CXCL1 - metabolism; Chemokine CXCL2 - metabolism; Enzymes; G-CSF; Granulocyte Colony-Stimulating Factor - metabolism; Homeostasis; Il-17; IL-17-producing T cells; Interleukin-17 - metabolism; Isoenzymes - deficiency; Isoenzymes - genetics; Isoenzymes - metabolism; Leukocyte Disorders - genetics; Leukocyte Disorders - metabolism; Lung - metabolism; Mice; Mice, Inbred C57BL; Neutrophilia; Neutrophils - metabolism; Phosphatidylinositol 3-Kinases - deficiency; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Physiological aspects; PI3K p110γ; PI3K p110δ,neutrophil homeostasis; Spleen - metabolism; T cells; T-Lymphocytes - metabolism; IL-17-producing T cells; G-CSF; Il-17; PI3K p110γ; PI3K p110δ,neutrophil homeostasis
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-017-0185-y

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.
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.
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.
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.