Bryan Petersen

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

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.

Pulmonary IL-17E (IL-25) Production and IL-17RB+ Myeloid Cell-Derived Th2 Cytokine Production Are Dependent upon Stem Cell Factor-Induced Responses during Chronic Allergic Pulmonary Disease

In the present studies local neutralization of allergen-induced stem cell factor (SCF) leads to decreased production of Th2 cytokines, a reduction in inflammation, allergen-specific serum IgE/IgG1, and attenuation of severe asthma-like responses. The local blockade of pulmonary SCF also resulted in a significant reduction of IL-17E (IL-25). Sorted cell populations from the lung indicated that IL-25 was produced from c-kit+ cells, whereas Th2 cytokine production was primarily from c-kit− cell populations. SCF stimulated c-kit+ eosinophils produced IL-25, whereas bone marrow-derived mast cells did not. Using 4get mice that contain a IL-4-IRES-eGFP that when transcribed coexpress GFP and IL-4, our studies identified cells that comprised a CD11b+, GR1+, Ly6C+/−, c-kit−, CD4−, CD11c−, MHC class IIlow cell population as a source of IL-4 in the lung after chronic allergen challenge. In the bone marrow a similar cell was identified with approximately a third of the IL-4+ cells also expressing c-kit+. The pulmonary and bone marrow IL-4+ cell populations were significantly reduced upon local pulmonary anti-SCF treatment. Subsequently, when IL-25R was examined during the chronic allergen responses the expression was found on the IL-4+ myeloid cell population that expressed CD11b+GR1+. Interestingly, the IL-25R+ cells in the bone marrow were also all CD11b+GR1+, similar to the lung cells, but they were also all c-kit+, potentially suggesting a maturation of the bone marrow cell once it enters the lung and/or is stimulated by SCF. Overall, these studies suggest a complex relationship between SCF, bone marrow-derived IL-25-responsive myeloid cells, Th2 cytokines, and chronic allergic disease.

IPS-1 signaling has a nonredundant role in mediating antiviral responses and the clearance of respiratory syncytial virus.

The cytosolic RNA helicases melanoma differentiation–associated gene 5 and retinoic acid–inducible gene-I and their adaptor IFN-β promoter stimulator (IPS-1) have been implicated in the recognition of viral RNA and the production of type I IFN. Complementing the endosomal TLR, melanoma differentiation–associated gene 5, and retinoic acid–inducible gene-I provides alternative mechanisms for viral detection in cells with reduced phagocytosis or autophagy. The infection route of respiratory syncytial virus (RSV)—via fusion of virus particles with the cell membrane—points to IPS-1 signaling as the pathway of choice for downstream antiviral responses. In the current study, viral clearance and inflammation resolution were indeed strongly affected by the absence of an initial IPS-1–mediated IFN-β response. Despite the blunted inflammatory response in IPS-1–deficient alveolar epithelial cells, pulmonary macrophages, and CD11b+ dendritic cells (DC), the lungs of RSV-infected IPS-1–knockout mice showed augmented recruitment of inflammatory neutrophils, monocytes, and DC. Interestingly, pulmonary CD103+ DC could functionally compensate for IPS-1 deficiency with the upregulation of certain inflammatory cytokines and chemokines, possibly via TLR3 and TLR7 signaling. The increased inflammation and reduced viral clearance in IPS-1–knockout mice was accompanied by increased T cell activation and IFN-γ production. Experiments with bone marrow chimeras indicated that RSV-induced lung pathology was most severe when IPS-1 expression was lacking in both immune and nonimmune cell populations. Similarly, viral clearance was rescued upon restored IPS-1 signaling in either the nonimmune or the immune compartment. These data support a nonredundant function for IPS-1 in controlling RSV-induced inflammation and viral replication.

IL-17E (IL-25) and IL-17RB promote respiratory syncytial virus-induced pulmonary disease

One of the most severe pathologic responses of RSV infection is associated with overproduction of cytokines and inflammation, leading to mucus hypersecretion. This study investigated the role of IL‐25 in the development of RSV‐associated immunopathology. IL‐25 and its receptor IL‐17RB were increased following RSV infection, and IL‐25 blockade using neutralizing antibodies reduced RSV‐associated pathology, AHR, and type 2 cytokine production. Likewise, IL‐17RB−/− mice demonstrated a modified inflammatory response during RSV infection characterized by decreased Th2 and increased Th17 cytokine production. Additionally, the IL‐17RB−/− mice demonstrated significantly reduced inflammation and cytokine production in a model of RSV‐driven asthma exacerbation. These results indicate that IL‐25 regulates the inflammatory response to RSV infection and that its inhibition may enable a reduction in the severity of RSV‐associated pulmonary inflammation, including during viral‐induced asthma exacerbation.

IL-25 induces type 2 cytokine production in a novel, steroid resistant IL-17RB+ myeloid population that exacerbates asthmatic pathology

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.

喘息インターロイキン25は喘息の病状を悪化させるステロイド抵抗性のインターロイキン-17RB+骨髄系細胞集団で2型サイトカインの産生を引き起こす

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.