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Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology.

ABSTRACT: Interleukin-25 (IL-25) is a cytokine associated with allergy and asthma that functions to promote type 2 immune responses at mucosal epithelial surfaces and serves to protect against helminth parasitic infections in the intestinal tract. This study identifies the IL-25 receptor, IL-17RB, as a key mediator of both innate and adaptive pulmonary type 2 immune responses. Allergen exposure upregulated IL-25 and induced type 2 cytokine production in a previously undescribed granulocytic population, termed type 2 myeloid (T2M) cells. Il17rb(-/-) mice showed reduced lung pathology after chronic allergen exposure and decreased type 2 cytokine production in T2M cells and CD4(+) T lymphocytes. Airway instillation of IL-25 induced IL-4 and IL-13 production in T2M cells, demonstrating their importance in eliciting T cell-independent inflammation. The adoptive transfer of T2M cells reconstituted IL-25-mediated responses in Il17rb(-/-) mice. High-dose dexamethasone treatment did not reduce the IL-25-induced T2M pulmonary response. Finally, a similar IL-4- and IL-13-producing granulocytic population was identified in peripheral blood of human subjects with asthma. These data establish IL-25 and its receptor IL-17RB as targets for innate and adaptive immune responses in chronic allergic airway disease and identify T2M cells as a new steroid-resistant cell population.

SUBMITTER: Petersen BC

PROVIDER: S-EPMC3378776 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology.

Petersen Bryan C BC Budelsky Alison L AL Baptist Alan P AP Schaller Matthew A MA Lukacs Nicholas W NW

Nature medicine 20120501 5

Interleukin-25 (IL-25) is a cytokine associated with allergy and asthma that functions to promote type 2 immune responses at mucosal epithelial surfaces and serves to protect against helminth parasitic infections in the intestinal tract. This study identifies the IL-25 receptor, IL-17RB, as a key mediator of both innate and adaptive pulmonary type 2 immune responses. Allergen exposure upregulated IL-25 and induced type 2 cytokine production in a previously undescribed granulocytic population, te ...[more]

PMID: 22543263

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Project description:Endophilin-B1, also known as Bax-interacting factor 1 (Bif-1, and encoded by SH3GLB1), is a multifunctional protein involved in apoptosis, autophagy and mitochondrial function. We recently described a unique neuroprotective role for neuron-specific alternatively spliced isoforms of endophilin-B1. To examine whether endophilin-B1-mediated neuroprotection could be a novel therapeutic target for Alzheimer's disease we used a double mutant amyloid precursor protein and presenilin 1 (APPswe/PSEN1dE9) mouse model of Alzheimer's disease and observed that expression of neuron-specific endophilin-B1 isoforms declined with disease progression. To determine if this reduction in endophilin-B1 has a functional role in Alzheimer's disease pathogenesis, we crossed endophilin-B1(-/-) mice with APPswe/PSEN1dE9 mice. Deletion of endophilin-B1 accelerated disease onset and progression in 6-month-old APPswe/PSEN1dE9/endophilin-B1(-/-) mice, which showed more plaques, astrogliosis, synaptic degeneration, cognitive impairment and mortality than APPswe/PSEN1dE9 mice. In mouse primary cortical neuron cultures, overexpression of neuron-specific endophilin-B1 isoforms protected against amyloid-β-induced apoptosis and mitochondrial dysfunction. Additionally, protein and mRNA levels of neuron-specific endophilin-B1 isoforms were also selectively decreased in the cerebral cortex and in the synaptic compartment of patients with Alzheimer's disease. Flow sorting of synaptosomes from patients with Alzheimer's disease demonstrated a negative correlation between amyloid-β and endophilin-B1 levels. The importance of endophilin-B1 in neuronal function was further underscored by the development of synaptic degeneration and cognitive and motor impairment in endophilin-B1(-/-) mice by 12 months. Our findings suggest that endophilin-B1 is a key mediator of a feed-forward mechanism of Alzheimer's disease pathogenesis where amyloid-β reduces neuron-specific endophilin-B1, which in turn enhances amyloid-β accumulation and neuronal vulnerability to stress.

Dataset Information

Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology.

Publications

Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology.

Similar Datasets

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