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IL-1?-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKK?.

ABSTRACT: Transcription factor NF-?B and its activating kinase IKK? are associated with inflammation and are believed to be critical for innate immunity. Despite the likelihood of immune suppression, pharmacological blockade of IKK?-NF-?B has been considered as a therapeutic strategy. However, we found neutrophilia in mice with inducible deletion of IKK? (Ikk?(?) mice). These mice had hyperproliferative granulocyte-macrophage progenitors and pregranulocytes and a prolonged lifespan of mature neutrophils that correlated with the induction of genes encoding prosurvival molecules. Deletion of interleukin 1 receptor 1 (IL-1R1) in Ikk?(?) mice normalized blood cellularity and prevented neutrophil-driven inflammation. However, Ikk?(?)Il1r1(-/-) mice, unlike Ikk?(?) mice, were highly susceptible to bacterial infection, which indicated that signaling via IKK?-NF-?B or IL-1R1 can maintain antimicrobial defenses in each other's absence, whereas inactivation of both pathways severely compromises innate immunity.

SUBMITTER: Hsu LC

PROVIDER: S-EPMC3677078 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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IL-1β-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKKβ.

Hsu Li-Chung LC Enzler Thomas T Seita Jun J Timmer Anjuli M AM Lee Chih-Yuan CY Lai Ting-Yu TY Yu Guann-Yi GY Lai Liang-Chuan LC Temkin Vladislav V Sinzig Ursula U Aung Thiha T Nizet Victor V Weissman Irving L IL Karin Michael M

Nature immunology 20101219 2

Transcription factor NF-κB and its activating kinase IKKβ are associated with inflammation and are believed to be critical for innate immunity. Despite the likelihood of immune suppression, pharmacological blockade of IKKβ-NF-κB has been considered as a therapeutic strategy. However, we found neutrophilia in mice with inducible deletion of IKKβ (Ikkβ(Δ) mice). These mice had hyperproliferative granulocyte-macrophage progenitors and pregranulocytes and a prolonged lifespan of mature neutrophils t ...[more]

PMID: 21170027

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Project description:BackgroundPhosphoinositide 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.MethodsNeutrophils 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.ResultsWe 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.ConclusionsWe 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.

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IL-1?-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKK?.

Publications

IL-1β-driven neutrophilia preserves antibacterial defense in the absence of the kinase IKKβ.

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