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Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy.

McSorley HJ, Blair NF, Smith KA, McKenzie AN, Maizels RM - Mucosal Immunol (2014)

Bottom Line: Here, we show that the soluble excretory/secretory products of H. polygyrus (HES) potently suppress inflammation induced by allergens from the common fungus Alternaria alternata.Administration of recombinant IL-33 at sensitization with Alternaria/OVA/HES abrogated HES suppression of OVA-specific responses at challenge, indicating that suppression of early Alternaria-induced IL-33 release could be central to the anti-allergic effects of HES.Thus, this helminth parasite targets IL-33 production as part of its armory of suppressive effects, forestalling the development of the type 2 immune response to infection and allergic sensitization.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

ABSTRACT
Helminth parasites such as the nematode Heligmosomoides polygyrus strongly inhibit T helper type 2 (Th2) allergy, as well as colitis and autoimmunity. Here, we show that the soluble excretory/secretory products of H. polygyrus (HES) potently suppress inflammation induced by allergens from the common fungus Alternaria alternata. Alternaria extract, when administered to mice intranasally with ovalbumin (OVA) protein, induces a rapid (1-48 h) innate response while also priming an OVA-specific Th2 response that can be evoked 14 days later by intranasal administration of OVA alone. In this model, HES coadministration with Alternaria/OVA suppressed early IL-33 release, innate lymphoid cell (ILC) production of IL-4, IL-5, and IL-13, and localized eosinophilia. Upon OVA challenge, type 2 ILC (ILC2)/Th2 cytokine production and eosinophilia were diminished in HES-treated mice. HES administration 6 h before Alternaria blocked the allergic response, and its suppressive activity was abolished by heat treatment. Administration of recombinant IL-33 at sensitization with Alternaria/OVA/HES abrogated HES suppression of OVA-specific responses at challenge, indicating that suppression of early Alternaria-induced IL-33 release could be central to the anti-allergic effects of HES. Thus, this helminth parasite targets IL-33 production as part of its armory of suppressive effects, forestalling the development of the type 2 immune response to infection and allergic sensitization.

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Suppression of innate and adaptive Type 2 responsiveness by HESFollowing Alternaria-OVA sensitization and challenge, BAL fluids, lungs and draining lymph nodes were collected; in some experiments (G-I), 1×106 DO11.10 OVA-specific T cells were transferred to mice prior to sensitization. Fluids were assayed for soluble cytokines and markers, and cells stained for cytokines and Foxp3.A. Cytokines in cell-free BAL supernatant measured by cytometric bead array.B. Type 2 myeloid cell response markers in BAL measured by ELISA.C-F. Intracellular cytokine-positive proportions (C and D) and absolute numbers (E and F) of lung CD4+TCRβ+ T cells (C and E) and ICOS+lineage− Innate Lymphoid Cells (D and F). Lung tissue cells were cultured in PMA/Ionomycin for 4 h in the presence of Brefeldin A, before staining for surface markers and intracellular cytokines.G. Intracellular IL-13 expression by ICOS+Lineage− lung cells.H. Intracellular IL-4 within DO11.10 OVA-specific T cells from the draining lymph nodes co-staining with the clonotypic marker KJ126.I. Intracellular Foxp3 expression in the draining lymph node CD4+KJ126+ T cell population.Results are representative or pooled from at least 2 repeat experiments with 3-5 mice per group. Unless otherwise indicated differences are not significant. *** = p<0.01, ** = p<0.01, * = p<0.05. # indicates significance when comparing Alt-OVA:PBS and Alt-OVA:OVA groups, * indicates significance when comparing Alt-OVA:OVA and Alt-OVA-HES:OVA groups in A-C, or as indicated by bars in D-J.
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Figure 2: Suppression of innate and adaptive Type 2 responsiveness by HESFollowing Alternaria-OVA sensitization and challenge, BAL fluids, lungs and draining lymph nodes were collected; in some experiments (G-I), 1×106 DO11.10 OVA-specific T cells were transferred to mice prior to sensitization. Fluids were assayed for soluble cytokines and markers, and cells stained for cytokines and Foxp3.A. Cytokines in cell-free BAL supernatant measured by cytometric bead array.B. Type 2 myeloid cell response markers in BAL measured by ELISA.C-F. Intracellular cytokine-positive proportions (C and D) and absolute numbers (E and F) of lung CD4+TCRβ+ T cells (C and E) and ICOS+lineage− Innate Lymphoid Cells (D and F). Lung tissue cells were cultured in PMA/Ionomycin for 4 h in the presence of Brefeldin A, before staining for surface markers and intracellular cytokines.G. Intracellular IL-13 expression by ICOS+Lineage− lung cells.H. Intracellular IL-4 within DO11.10 OVA-specific T cells from the draining lymph nodes co-staining with the clonotypic marker KJ126.I. Intracellular Foxp3 expression in the draining lymph node CD4+KJ126+ T cell population.Results are representative or pooled from at least 2 repeat experiments with 3-5 mice per group. Unless otherwise indicated differences are not significant. *** = p<0.01, ** = p<0.01, * = p<0.05. # indicates significance when comparing Alt-OVA:PBS and Alt-OVA:OVA groups, * indicates significance when comparing Alt-OVA:OVA and Alt-OVA-HES:OVA groups in A-C, or as indicated by bars in D-J.

Mentions: The allergic response in OVA-Alternaria-primed mice displayed all the canonical features of Type 2 immune responsiveness. Thus, the Type 2 cytokines IL-4 and IL-5 were significantly upregulated in BAL supernatants from allergic mice, along with a trend for increased IL-13 (Fig. 2 A). In mice receiving HES at priming, these cytokine responses were suppressed without any evident switch to IFN-γ or IL-17A (Fig. 2 A). BAL fluids also contained elevated levels of the type 2 myeloid cell response markers RELM-α and Ym1 34 which were again suppressed by HES coadministration, although only significantly so in the case of RELM-α (Fig. 2 B).


Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy.

McSorley HJ, Blair NF, Smith KA, McKenzie AN, Maizels RM - Mucosal Immunol (2014)

Suppression of innate and adaptive Type 2 responsiveness by HESFollowing Alternaria-OVA sensitization and challenge, BAL fluids, lungs and draining lymph nodes were collected; in some experiments (G-I), 1×106 DO11.10 OVA-specific T cells were transferred to mice prior to sensitization. Fluids were assayed for soluble cytokines and markers, and cells stained for cytokines and Foxp3.A. Cytokines in cell-free BAL supernatant measured by cytometric bead array.B. Type 2 myeloid cell response markers in BAL measured by ELISA.C-F. Intracellular cytokine-positive proportions (C and D) and absolute numbers (E and F) of lung CD4+TCRβ+ T cells (C and E) and ICOS+lineage− Innate Lymphoid Cells (D and F). Lung tissue cells were cultured in PMA/Ionomycin for 4 h in the presence of Brefeldin A, before staining for surface markers and intracellular cytokines.G. Intracellular IL-13 expression by ICOS+Lineage− lung cells.H. Intracellular IL-4 within DO11.10 OVA-specific T cells from the draining lymph nodes co-staining with the clonotypic marker KJ126.I. Intracellular Foxp3 expression in the draining lymph node CD4+KJ126+ T cell population.Results are representative or pooled from at least 2 repeat experiments with 3-5 mice per group. Unless otherwise indicated differences are not significant. *** = p<0.01, ** = p<0.01, * = p<0.05. # indicates significance when comparing Alt-OVA:PBS and Alt-OVA:OVA groups, * indicates significance when comparing Alt-OVA:OVA and Alt-OVA-HES:OVA groups in A-C, or as indicated by bars in D-J.
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Related In: Results  -  Collection

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Figure 2: Suppression of innate and adaptive Type 2 responsiveness by HESFollowing Alternaria-OVA sensitization and challenge, BAL fluids, lungs and draining lymph nodes were collected; in some experiments (G-I), 1×106 DO11.10 OVA-specific T cells were transferred to mice prior to sensitization. Fluids were assayed for soluble cytokines and markers, and cells stained for cytokines and Foxp3.A. Cytokines in cell-free BAL supernatant measured by cytometric bead array.B. Type 2 myeloid cell response markers in BAL measured by ELISA.C-F. Intracellular cytokine-positive proportions (C and D) and absolute numbers (E and F) of lung CD4+TCRβ+ T cells (C and E) and ICOS+lineage− Innate Lymphoid Cells (D and F). Lung tissue cells were cultured in PMA/Ionomycin for 4 h in the presence of Brefeldin A, before staining for surface markers and intracellular cytokines.G. Intracellular IL-13 expression by ICOS+Lineage− lung cells.H. Intracellular IL-4 within DO11.10 OVA-specific T cells from the draining lymph nodes co-staining with the clonotypic marker KJ126.I. Intracellular Foxp3 expression in the draining lymph node CD4+KJ126+ T cell population.Results are representative or pooled from at least 2 repeat experiments with 3-5 mice per group. Unless otherwise indicated differences are not significant. *** = p<0.01, ** = p<0.01, * = p<0.05. # indicates significance when comparing Alt-OVA:PBS and Alt-OVA:OVA groups, * indicates significance when comparing Alt-OVA:OVA and Alt-OVA-HES:OVA groups in A-C, or as indicated by bars in D-J.
Mentions: The allergic response in OVA-Alternaria-primed mice displayed all the canonical features of Type 2 immune responsiveness. Thus, the Type 2 cytokines IL-4 and IL-5 were significantly upregulated in BAL supernatants from allergic mice, along with a trend for increased IL-13 (Fig. 2 A). In mice receiving HES at priming, these cytokine responses were suppressed without any evident switch to IFN-γ or IL-17A (Fig. 2 A). BAL fluids also contained elevated levels of the type 2 myeloid cell response markers RELM-α and Ym1 34 which were again suppressed by HES coadministration, although only significantly so in the case of RELM-α (Fig. 2 B).

Bottom Line: Here, we show that the soluble excretory/secretory products of H. polygyrus (HES) potently suppress inflammation induced by allergens from the common fungus Alternaria alternata.Administration of recombinant IL-33 at sensitization with Alternaria/OVA/HES abrogated HES suppression of OVA-specific responses at challenge, indicating that suppression of early Alternaria-induced IL-33 release could be central to the anti-allergic effects of HES.Thus, this helminth parasite targets IL-33 production as part of its armory of suppressive effects, forestalling the development of the type 2 immune response to infection and allergic sensitization.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.

ABSTRACT
Helminth parasites such as the nematode Heligmosomoides polygyrus strongly inhibit T helper type 2 (Th2) allergy, as well as colitis and autoimmunity. Here, we show that the soluble excretory/secretory products of H. polygyrus (HES) potently suppress inflammation induced by allergens from the common fungus Alternaria alternata. Alternaria extract, when administered to mice intranasally with ovalbumin (OVA) protein, induces a rapid (1-48 h) innate response while also priming an OVA-specific Th2 response that can be evoked 14 days later by intranasal administration of OVA alone. In this model, HES coadministration with Alternaria/OVA suppressed early IL-33 release, innate lymphoid cell (ILC) production of IL-4, IL-5, and IL-13, and localized eosinophilia. Upon OVA challenge, type 2 ILC (ILC2)/Th2 cytokine production and eosinophilia were diminished in HES-treated mice. HES administration 6 h before Alternaria blocked the allergic response, and its suppressive activity was abolished by heat treatment. Administration of recombinant IL-33 at sensitization with Alternaria/OVA/HES abrogated HES suppression of OVA-specific responses at challenge, indicating that suppression of early Alternaria-induced IL-33 release could be central to the anti-allergic effects of HES. Thus, this helminth parasite targets IL-33 production as part of its armory of suppressive effects, forestalling the development of the type 2 immune response to infection and allergic sensitization.

Show MeSH
Related in: MedlinePlus