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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 induces a rapid innate eosinophilia and ILC2 response which is suppressed by HESAlternaria, without OVA, was administered intransally to BALB/c mice (A, B-H, K), IL-13-GFP reporter mice (B) or RAG-2-deficient mice (I, J) in the presence or absence of HES, and samples harvested 24 or 48 hours later.A. B. BAL (A) and lung (B) eosinophils measured 24 and 48 h after administration of Alternaria with or without HES.C. Expression of IL-13-GFP in reporter mice 20 48 h following administration of Alternaria with or without HES, measured in lung ICOS+Lineage− cells.D-F. Lung ICOS+Lineage− cell expression of IL-4 (D), IL-5 (E) or IL-13 (F), measured by intracellular staining.G, H. BAL eosinophils (G) and intracellular IL-13+ proportion of ICOS+Lineage− cells (H) measured at 24 and 48 h following administration of Alternaria with or without HES or heat-treated HES (HT-HES). Significance shown are compared to the Alternaria + HT-HES groupI. BALB/c mice were treated with Alternaria with or without HES or 4 ng recombinant mammalian TGF-β, and BAL eosinophils measured by flow cytometry.J, K. BAL eosinophils (J) and IL-13 expression by ILCs (K) were measured 48h after administration of Alternaria with or without HES to RAG-deficient mice.L. BAL eosinophils 48h after administration of HES with, or 6 hours before, Alternaria exposure.Results are representative or pooled from at least 2 repeat experiments, 3-5 mice per group. Unless otherwise indicated differences are not significant. *** = p<0.01, ** = p<0.01, * = p<0.05.
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Figure 4: Alternaria induces a rapid innate eosinophilia and ILC2 response which is suppressed by HESAlternaria, without OVA, was administered intransally to BALB/c mice (A, B-H, K), IL-13-GFP reporter mice (B) or RAG-2-deficient mice (I, J) in the presence or absence of HES, and samples harvested 24 or 48 hours later.A. B. BAL (A) and lung (B) eosinophils measured 24 and 48 h after administration of Alternaria with or without HES.C. Expression of IL-13-GFP in reporter mice 20 48 h following administration of Alternaria with or without HES, measured in lung ICOS+Lineage− cells.D-F. Lung ICOS+Lineage− cell expression of IL-4 (D), IL-5 (E) or IL-13 (F), measured by intracellular staining.G, H. BAL eosinophils (G) and intracellular IL-13+ proportion of ICOS+Lineage− cells (H) measured at 24 and 48 h following administration of Alternaria with or without HES or heat-treated HES (HT-HES). Significance shown are compared to the Alternaria + HT-HES groupI. BALB/c mice were treated with Alternaria with or without HES or 4 ng recombinant mammalian TGF-β, and BAL eosinophils measured by flow cytometry.J, K. BAL eosinophils (J) and IL-13 expression by ILCs (K) were measured 48h after administration of Alternaria with or without HES to RAG-deficient mice.L. BAL eosinophils 48h after administration of HES with, or 6 hours before, Alternaria exposure.Results are representative or pooled from at least 2 repeat experiments, 3-5 mice per group. Unless otherwise indicated differences are not significant. *** = p<0.01, ** = p<0.01, * = p<0.05.

Mentions: Alternaria administration is known to induce ILC2 responses and eosinophil accumulation in the first days after administration, in a mechanism dependent on IL-33 signalling, prior to and independent of involvement of the adaptive immune system 7, 17. We therefore tracked the immune response over the first 48 h following in vivo exposure to Alternaria and HES. In this setting, HES coadministration completely ablated the BAL and lung eosinophil response to Alternaria (Fig. 4 A, B). To accurately assay ILC2 activation (in the absence of PMA/Ionomycin stimulation), we administered Alternaria/HES to IL-13-GFP reporter mice, and found substantial suppression by HES of the expansion of IL-13-GFP+ positive ILC2s at 48 h post-administration which were lineage-negative but ICOS+, CD44+ and CD25+ (Fig. 4 C and Supplementary Fig. 5). We also assessed ILC2 intracellular cytokine production over the first 48 h after Alternaria/HES administration and found decreased ILC2 production of IL-4, IL-5 and IL-13 (Fig. 4 D-F). As in the Alternaria-OVA model, when HES was heat-treated, it lost its ability to suppress early eosinophilia and ILC2 IL-13 production (Fig 4 G, H). To address the role of the TGF-β mimic in HES, we again administered recombinant TGF-β, and were not able to replicate the suppressive effect of HES (Fig 4 I). To discount any T cell contribution to this effect, we repeated the exposure in RAG-deficient mice; despite the absence of adaptive lymphocytes, marked eosinophilia (Fig. 4 J) and ILC2 expression of IL-13 was observed at 48 hours following Alternaria administration (Fig. 4 K), both of which were suppressed by HES. In addition, we were able to exclude a physical effect, such as digestion, of HES upon Alternaria extract by replicating suppression in mice given HES 6 hours prior to the separate administration of Alternaria(Fig. 4 L).


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 induces a rapid innate eosinophilia and ILC2 response which is suppressed by HESAlternaria, without OVA, was administered intransally to BALB/c mice (A, B-H, K), IL-13-GFP reporter mice (B) or RAG-2-deficient mice (I, J) in the presence or absence of HES, and samples harvested 24 or 48 hours later.A. B. BAL (A) and lung (B) eosinophils measured 24 and 48 h after administration of Alternaria with or without HES.C. Expression of IL-13-GFP in reporter mice 20 48 h following administration of Alternaria with or without HES, measured in lung ICOS+Lineage− cells.D-F. Lung ICOS+Lineage− cell expression of IL-4 (D), IL-5 (E) or IL-13 (F), measured by intracellular staining.G, H. BAL eosinophils (G) and intracellular IL-13+ proportion of ICOS+Lineage− cells (H) measured at 24 and 48 h following administration of Alternaria with or without HES or heat-treated HES (HT-HES). Significance shown are compared to the Alternaria + HT-HES groupI. BALB/c mice were treated with Alternaria with or without HES or 4 ng recombinant mammalian TGF-β, and BAL eosinophils measured by flow cytometry.J, K. BAL eosinophils (J) and IL-13 expression by ILCs (K) were measured 48h after administration of Alternaria with or without HES to RAG-deficient mice.L. BAL eosinophils 48h after administration of HES with, or 6 hours before, Alternaria exposure.Results are representative or pooled from at least 2 repeat experiments, 3-5 mice per group. Unless otherwise indicated differences are not significant. *** = p<0.01, ** = p<0.01, * = p<0.05.
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Figure 4: Alternaria induces a rapid innate eosinophilia and ILC2 response which is suppressed by HESAlternaria, without OVA, was administered intransally to BALB/c mice (A, B-H, K), IL-13-GFP reporter mice (B) or RAG-2-deficient mice (I, J) in the presence or absence of HES, and samples harvested 24 or 48 hours later.A. B. BAL (A) and lung (B) eosinophils measured 24 and 48 h after administration of Alternaria with or without HES.C. Expression of IL-13-GFP in reporter mice 20 48 h following administration of Alternaria with or without HES, measured in lung ICOS+Lineage− cells.D-F. Lung ICOS+Lineage− cell expression of IL-4 (D), IL-5 (E) or IL-13 (F), measured by intracellular staining.G, H. BAL eosinophils (G) and intracellular IL-13+ proportion of ICOS+Lineage− cells (H) measured at 24 and 48 h following administration of Alternaria with or without HES or heat-treated HES (HT-HES). Significance shown are compared to the Alternaria + HT-HES groupI. BALB/c mice were treated with Alternaria with or without HES or 4 ng recombinant mammalian TGF-β, and BAL eosinophils measured by flow cytometry.J, K. BAL eosinophils (J) and IL-13 expression by ILCs (K) were measured 48h after administration of Alternaria with or without HES to RAG-deficient mice.L. BAL eosinophils 48h after administration of HES with, or 6 hours before, Alternaria exposure.Results are representative or pooled from at least 2 repeat experiments, 3-5 mice per group. Unless otherwise indicated differences are not significant. *** = p<0.01, ** = p<0.01, * = p<0.05.
Mentions: Alternaria administration is known to induce ILC2 responses and eosinophil accumulation in the first days after administration, in a mechanism dependent on IL-33 signalling, prior to and independent of involvement of the adaptive immune system 7, 17. We therefore tracked the immune response over the first 48 h following in vivo exposure to Alternaria and HES. In this setting, HES coadministration completely ablated the BAL and lung eosinophil response to Alternaria (Fig. 4 A, B). To accurately assay ILC2 activation (in the absence of PMA/Ionomycin stimulation), we administered Alternaria/HES to IL-13-GFP reporter mice, and found substantial suppression by HES of the expansion of IL-13-GFP+ positive ILC2s at 48 h post-administration which were lineage-negative but ICOS+, CD44+ and CD25+ (Fig. 4 C and Supplementary Fig. 5). We also assessed ILC2 intracellular cytokine production over the first 48 h after Alternaria/HES administration and found decreased ILC2 production of IL-4, IL-5 and IL-13 (Fig. 4 D-F). As in the Alternaria-OVA model, when HES was heat-treated, it lost its ability to suppress early eosinophilia and ILC2 IL-13 production (Fig 4 G, H). To address the role of the TGF-β mimic in HES, we again administered recombinant TGF-β, and were not able to replicate the suppressive effect of HES (Fig 4 I). To discount any T cell contribution to this effect, we repeated the exposure in RAG-deficient mice; despite the absence of adaptive lymphocytes, marked eosinophilia (Fig. 4 J) and ILC2 expression of IL-13 was observed at 48 hours following Alternaria administration (Fig. 4 K), both of which were suppressed by HES. In addition, we were able to exclude a physical effect, such as digestion, of HES upon Alternaria extract by replicating suppression in mice given HES 6 hours prior to the separate administration of Alternaria(Fig. 4 L).

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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Related in: MedlinePlus