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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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Alternaria-induced allergic inflammation to Ovalbumin (OVA) challenge is suppressed by H. polygyrus Excretory-Secretory (HES) productsA. Schematic of the Alternaria model: OVA protein (20 μg) was administered to BALB/c mice intranasally, with or without 50 μg Alternaria extract and 10 μg HES. Two weeks later mice were challenged by intranasal (i.n.) administration of 20 μg OVA or PBS for 3 days, and samples taken at day 17.B. Numbers of SiglecF+CD11c− eosinophils in bronchoalveolar lavage (BAL) fluid determined by flow cytometry.C, D. Lung cell suspensions were analyzed by flow cytometry for eosinophils (as in B) and neutrophils (GR1hiCD11bhiSiglecf−CD11c−).E. Formalin-fixed lungs were sectioned and stained by Hemotoxylin and Eosin (H&E) or Periodic Acid Schiff (PAS). Representative sections are presented, scale bar = 100 μm.F. HES was heat-treated at 95°C for 20 min (HT-HES) prior to administration, and numbers of BAL SiglecF+CD11c− eosinophils counted.G. BAL eosinophils from mice treated with Alternaria, OVA and HES as described in A, or with 4 ng rTGF-β (TGF), or 10 μg BSA as indicated.Data in (B-D) are representative of 5 repeat experiments, 3-5 per mice group, in (F) are pooled from 2 repeat experiments, total n=7 per group and in (G) are representative of 2 repeat experiments with 4 mice per group. *** = p<0.001, ** = p<0.01, * = p<0.05, N.S. = Not significant
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Figure 1: Alternaria-induced allergic inflammation to Ovalbumin (OVA) challenge is suppressed by H. polygyrus Excretory-Secretory (HES) productsA. Schematic of the Alternaria model: OVA protein (20 μg) was administered to BALB/c mice intranasally, with or without 50 μg Alternaria extract and 10 μg HES. Two weeks later mice were challenged by intranasal (i.n.) administration of 20 μg OVA or PBS for 3 days, and samples taken at day 17.B. Numbers of SiglecF+CD11c− eosinophils in bronchoalveolar lavage (BAL) fluid determined by flow cytometry.C, D. Lung cell suspensions were analyzed by flow cytometry for eosinophils (as in B) and neutrophils (GR1hiCD11bhiSiglecf−CD11c−).E. Formalin-fixed lungs were sectioned and stained by Hemotoxylin and Eosin (H&E) or Periodic Acid Schiff (PAS). Representative sections are presented, scale bar = 100 μm.F. HES was heat-treated at 95°C for 20 min (HT-HES) prior to administration, and numbers of BAL SiglecF+CD11c− eosinophils counted.G. BAL eosinophils from mice treated with Alternaria, OVA and HES as described in A, or with 4 ng rTGF-β (TGF), or 10 μg BSA as indicated.Data in (B-D) are representative of 5 repeat experiments, 3-5 per mice group, in (F) are pooled from 2 repeat experiments, total n=7 per group and in (G) are representative of 2 repeat experiments with 4 mice per group. *** = p<0.001, ** = p<0.01, * = p<0.05, N.S. = Not significant

Mentions: Mice were sensitized by intranasal administration of OVA protein with extract of the fungal organism Alternaria alternata, and the OVA-specific response was measured following intranasal delivery of OVA protein alone 14 days later (Fig. 1A). OVA challenge elicited a substantial eosinophilic infiltrate in the bronchoalveolar lavage (BAL) and lung tissue of mice which had been primed with OVA in the presence of Alternaria (Fig. 1 B, C and Suppl. Fig. 1), while little change in neutrophils was observed (Fig. 1 D). No inflammation was seen in mice primed with soluble OVA alone, and only slight infiltration in animals receiving a PBS sham airway challenge (Fig. 1 E).


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)

Alternaria-induced allergic inflammation to Ovalbumin (OVA) challenge is suppressed by H. polygyrus Excretory-Secretory (HES) productsA. Schematic of the Alternaria model: OVA protein (20 μg) was administered to BALB/c mice intranasally, with or without 50 μg Alternaria extract and 10 μg HES. Two weeks later mice were challenged by intranasal (i.n.) administration of 20 μg OVA or PBS for 3 days, and samples taken at day 17.B. Numbers of SiglecF+CD11c− eosinophils in bronchoalveolar lavage (BAL) fluid determined by flow cytometry.C, D. Lung cell suspensions were analyzed by flow cytometry for eosinophils (as in B) and neutrophils (GR1hiCD11bhiSiglecf−CD11c−).E. Formalin-fixed lungs were sectioned and stained by Hemotoxylin and Eosin (H&E) or Periodic Acid Schiff (PAS). Representative sections are presented, scale bar = 100 μm.F. HES was heat-treated at 95°C for 20 min (HT-HES) prior to administration, and numbers of BAL SiglecF+CD11c− eosinophils counted.G. BAL eosinophils from mice treated with Alternaria, OVA and HES as described in A, or with 4 ng rTGF-β (TGF), or 10 μg BSA as indicated.Data in (B-D) are representative of 5 repeat experiments, 3-5 per mice group, in (F) are pooled from 2 repeat experiments, total n=7 per group and in (G) are representative of 2 repeat experiments with 4 mice per group. *** = p<0.001, ** = p<0.01, * = p<0.05, N.S. = Not significant
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Related In: Results  -  Collection

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Figure 1: Alternaria-induced allergic inflammation to Ovalbumin (OVA) challenge is suppressed by H. polygyrus Excretory-Secretory (HES) productsA. Schematic of the Alternaria model: OVA protein (20 μg) was administered to BALB/c mice intranasally, with or without 50 μg Alternaria extract and 10 μg HES. Two weeks later mice were challenged by intranasal (i.n.) administration of 20 μg OVA or PBS for 3 days, and samples taken at day 17.B. Numbers of SiglecF+CD11c− eosinophils in bronchoalveolar lavage (BAL) fluid determined by flow cytometry.C, D. Lung cell suspensions were analyzed by flow cytometry for eosinophils (as in B) and neutrophils (GR1hiCD11bhiSiglecf−CD11c−).E. Formalin-fixed lungs were sectioned and stained by Hemotoxylin and Eosin (H&E) or Periodic Acid Schiff (PAS). Representative sections are presented, scale bar = 100 μm.F. HES was heat-treated at 95°C for 20 min (HT-HES) prior to administration, and numbers of BAL SiglecF+CD11c− eosinophils counted.G. BAL eosinophils from mice treated with Alternaria, OVA and HES as described in A, or with 4 ng rTGF-β (TGF), or 10 μg BSA as indicated.Data in (B-D) are representative of 5 repeat experiments, 3-5 per mice group, in (F) are pooled from 2 repeat experiments, total n=7 per group and in (G) are representative of 2 repeat experiments with 4 mice per group. *** = p<0.001, ** = p<0.01, * = p<0.05, N.S. = Not significant
Mentions: Mice were sensitized by intranasal administration of OVA protein with extract of the fungal organism Alternaria alternata, and the OVA-specific response was measured following intranasal delivery of OVA protein alone 14 days later (Fig. 1A). OVA challenge elicited a substantial eosinophilic infiltrate in the bronchoalveolar lavage (BAL) and lung tissue of mice which had been primed with OVA in the presence of Alternaria (Fig. 1 B, C and Suppl. Fig. 1), while little change in neutrophils was observed (Fig. 1 D). No inflammation was seen in mice primed with soluble OVA alone, and only slight infiltration in animals receiving a PBS sham airway challenge (Fig. 1 E).

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