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Deficiency of PI3-Kinase catalytic isoforms p110? and p110? in mice enhances the IL-17/G-CSF axis and induces neutrophilia.


ABSTRACT:

Background

Phosphoinositide 3-kinase ? (PI3K?) and PI3K? are second messenger-generating enzymes with key roles in proliferation, differentiation, survival, and function of leukocytes. Deficiency of the catalytic subunits p110? and p110? of PI3K? and PI3K? in p110?/?-/- mice leads to defective B- and T-cell homeostasis. Here we examined the role of p110? and p110? in the homeostasis of neutrophils by analyzing p110?-/-, p110?-/- and p110?/?-/- 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, p110?/?-/- mice exhibited significantly elevated neutrophil counts in blood, spleen, and lung. Increased granulocytic differentiation stages in the bone marrow of p110?/?-/- 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 p110?/?-/- mice. Moreover, IFN-?+, IL-4+, and IL-5+ T cell subsets were drastically increased in p110?/?-/- 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 p110?/? deficiency in mice induces complex immunological changes, which might in concert contribute to neutrophilia. These findings emphasize a crucial but indirect role of both p110? and p110? in the regulation of neutrophil homeostasis.

SUBMITTER: Bucher K 

PROVIDER: S-EPMC5518148 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Bucher Kirsten K   Schmitt Fee F   Mothes Benedikt B   Blumendeller Carolin C   Schäll Daniel D   Piekorz Roland R   Hirsch Emilio E   Nürnberg Bernd B   Beer-Hammer Sandra S  

Cell communication and signaling : CCS 20170719 1


<h4>Background</h4>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<sup>-/-</sup> 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<sup>-/-</sup>, p110δ<sup>-/-</sup> and p110γ/δ<sup>-/-</sup>  ...[more]

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