An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products

Eicosanoids are key mediators of type-2 inflammation, e.g., in allergy and asthma. Helminth products have been suggested as remedies against inflammatory diseases, but their effects on eicosanoids are unknown. Here, we show that larval products of the helminth Heligmosomoides polygyrus bakeri (HpbE), known to modulate type-2 responses, trigger a broad anti-inflammatory eicosanoid shift by suppressing the 5-lipoxygenase pathway, but inducing the cyclooxygenase (COX) pathway. In human macrophages and granulocytes, the HpbE-driven induction of the COX pathway resulted in the production of anti-inflammatory mediators [e.g., prostaglandin E2 (PGE2) and IL-10] and suppressed chemotaxis. HpbE also abrogated the chemotaxis of granulocytes from patients suffering from aspirin-exacerbated respiratory disease (AERD), a severe type-2 inflammatory condition. Intranasal treatment with HpbE extract attenuated allergic airway inflammation in mice, and intranasal transfer of HpbE-conditioned macrophages led to reduced airway eosinophilia in a COX/PGE2-dependent fashion. The induction of regulatory mediators in macrophages depended on p38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1α (HIF-1α), and Hpb glutamate dehydrogenase (GDH), which we identify as a major immunoregulatory protein in HpbE. Hpb GDH activity was required for anti-inflammatory effects of HpbE in macrophages, and local administration of recombinant Hpb GDH to the airways abrogated allergic airway inflammation in mice. Thus, a metabolic enzyme present in helminth larvae can suppress type-2 inflammation by inducing an anti-inflammatory eicosanoid switch, which has important implications for the therapy of allergy and asthma.

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Chitinase 3-like-1 protects airway function despite promoting type 2 inflammation during fungal-associated allergic airway inflammation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00528.2020 ◽

2021 ◽

Author(s):

Joseph J. Mackel ◽

Jaleesa M. Garth ◽

MaryJane Jones ◽

Diandra A. Ellis ◽

Jonathan P. Blackburn ◽

...

Keyword(s):

Airway Inflammation ◽

Periodic Acid ◽

Acute Infection ◽

Allergic Bronchopulmonary Aspergillosis ◽

Allergic Airway Inflammation ◽

Lung Edema ◽

Periodic Acid Schiff ◽

Wide Range ◽

Type 2 Inflammation

Exposure to fungi can result in a wide range of comorbidities depending on the immune status of the host. Chronic exposure and reactivity to fungi such as Aspergillus fumigatus can result in conditions such as severe asthma with fungal sensitization (SAFS) or allergic bronchopulmonary aspergillosis (ABPA). However, the pathophysiology of SAFS and ABPA are not well understood. Here, we report that the chitinase-like protein YKL-40 is elevated in lung lavage fluid from human asthmatics that are sensitized to fungi. Initial studies demonstrated that mice deficient in the murine ortholog of YKL-40, breast regression protein-39 (BRP-39, chitinase-3-like 1, Chi3l1), were not more susceptible to acute infection with A. fumigatus. However, in an experimental model of fungal-associated allergic airway inflammation (fungal asthma), Chi3l1-/- mice had significantly increased airway hyperresponsiveness (AHR). Surprisingly, increased AHR in Chi3l1-/- mice occurred in the presence of significantly lower type 2 responses (decreased eosinophil numbers and decreased IL-4, IL-5, IL-33, CCL17 and CCL22 levels), although type 1 and type 17 responses were not different. Increased AHR was not associated with differences in Periodic-acid-Schiff staining of lung tissue, differences in the expression of Muc5ac and Clca3, nor differences in lung edema. Bone marrow chimera studies revealed that the presence of BRP-39 in either the hematopoietic or non-hematopoietic compartment was sufficient for controlling AHR during fungal asthma. Collectively, these results indicate that BRP-39 protects against AHR during fungal asthma despite contributing to type 2 inflammation, thus highlighting an unexpected protective role for BRP-39 in allergic fungal asthma.

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Contrasting roles for the receptor for advanced glycation end-products on structural cells in allergic airway inflammation vs. airway hyperresponsiveness

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00087.2015 ◽

2015 ◽

Vol 309 (8) ◽

pp. L789-L800 ◽

Cited By ~ 13

Author(s):

Akihiko Taniguchi ◽

Nobuaki Miyahara ◽

Koichi Waseda ◽

Etsuko Kurimoto ◽

Utako Fujii ◽

...

Keyword(s):

Airway Inflammation ◽

Airway Hyperresponsiveness ◽

Allergic Airway Inflammation ◽

T Helper ◽

Advanced Glycation ◽

Glycation End Products ◽

End Products ◽

Group 2 ◽

Airway Responses

The receptor for advanced glycation end-products (RAGE) is a multiligand receptor that belongs to the immunoglobulin superfamily. RAGE is reported to be involved in various inflammatory disorders; however, studies that address the role of RAGE in allergic airway disease are inconclusive. RAGE-sufficient (RAGE+/+) and RAGE-deficient (RAGE−/−) mice were sensitized to ovalbumin, and airway responses were monitored after ovalbumin challenge. RAGE−/− mice showed reduced eosinophilic inflammation and goblet cell metaplasia, lower T helper type 2 (Th2) cytokine production from spleen and peribronchial lymph node mononuclear cells, and lower numbers of group 2 innate lymphoid cells in the lung compared with RAGE+/+ mice following sensitization and challenge. Experiments using irradiated, chimeric mice showed that the mice expressing RAGE on radio-resistant structural cells but not hematopoietic cells developed allergic airway inflammation; however, the mice expressing RAGE on hematopoietic cells but not structural cells showed reduced airway inflammation. In contrast, absence of RAGE expression on structural cells enhanced innate airway hyperresponsiveness (AHR). In the absence of RAGE, increased interleukin (IL)-33 levels in the lung were detected, and blockade of IL-33 receptor ST2 suppressed innate AHR in RAGE−/− mice. These data identify the importance of RAGE expressed on lung structural cells in the development of allergic airway inflammation, T helper type 2 cell activation, and group 2 innate lymphoid cell accumulation in the airways. RAGE on lung structural cells also regulated innate AHR, likely through the IL-33-ST2 pathway. Thus manipulating RAGE represents a novel therapeutic target in controlling allergic airway responses.

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2-Deoxy-d-Glucose Treatment Decreases Anti-inflammatory M2 Macrophage Polarization in Mice with Tumor and Allergic Airway Inflammation

Frontiers in Immunology ◽

10.3389/fimmu.2017.00637 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 20

Author(s):

Qingjie Zhao ◽

Zhulang Chu ◽

Linnan Zhu ◽

Tao Yang ◽

Peng Wang ◽

...

Keyword(s):

Airway Inflammation ◽

Macrophage Polarization ◽

Allergic Airway Inflammation ◽

M2 Macrophage ◽

M2 Macrophage Polarization ◽

Glucose Treatment ◽

Anti Inflammatory

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IFITM proteins drive type 2 T helper cell differentiation and exacerbate allergic airway inflammation

European Journal of Immunology ◽

10.1002/eji.201847692 ◽

2018 ◽

Vol 49 (1) ◽

pp. 66-78 ◽

Cited By ~ 11

Author(s):

Diana C. Yánez ◽

Hemant Sahni ◽

Susan Ross ◽

Anisha Solanki ◽

Ching-In Lau ◽

...

Keyword(s):

Cell Differentiation ◽

Airway Inflammation ◽

Allergic Airway Inflammation ◽

T Helper Cell ◽

Helper Cell ◽

T Helper

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The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation

Nature Communications ◽

10.1038/s41467-018-03886-6 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 23

Author(s):

Morris Nechama ◽

Jeahoo Kwon ◽

Shuo Wei ◽

Adrian Tun Kyi ◽

Robert S. Welner ◽

...

Keyword(s):

Airway Inflammation ◽

Allergic Airway Inflammation ◽

Type 2 Immunity

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Exposure to low-dose bisphenol A during the juvenile period of development disrupts the immune system and aggravates allergic airway inflammation in mice

International Journal of Immunopathology and Pharmacology ◽

10.1177/2058738418774897 ◽

2018 ◽

Vol 32 ◽

pp. 205873841877489 ◽

Cited By ~ 16

Author(s):

Eiko Koike ◽

Rie Yanagisawa ◽

Tin-Tin Win-Shwe ◽

Hirohisa Takano

Keyword(s):

Immune System ◽

Bisphenol A ◽

Airway Inflammation ◽

Low Dose ◽

Allergic Airway Inflammation ◽

Lymphoid Tissues ◽

Th2 Cytokines ◽

Juvenile Period ◽

Specific Immunoglobulin ◽

Anti Inflammatory

Bisphenol A (BPA) is used in the production of polycarbonate plastics and epoxy resins and found in many consumer products. Previous studies have reported that perinatal exposure to BPA through the oral route promotes the development of allergic airway inflammation. We investigated the effects of exposure to low-dose BPA during the juvenile period of development on allergic airway inflammation. Six-week-old male C3H/HeJ mice were intratracheally administered ovalbumin (OVA, 1 μg) every 2 weeks and/or BPA (0, 0.0625, 1.25, and 25 pmol/animal/week) once per week for 6 weeks. Following the final intratracheal instillation, we examined the cellular profile of the bronchoalveolar lavage fluid, histological changes and expression of inflammatory/anti-inflammatory mediators in the lungs, OVA-specific immunoglobulin (Ig) production, serum corticosterone levels, and changes in the lymphoid tissues (mediastinal lymph node (MLN) and spleen). Exposure to OVA + BPA enhanced inflammatory cell infiltration and protein expression of Th2 cytokines/chemokines (e.g. interleukin (IL)-13 and IL-33) in the lungs, OVA-specific immunoglobulin E (IgE) production, the numbers of total cells and activated antigen-presenting cells (MHC class II+ CD86+, CD11c+), as well as the production of Th2 cytokines (i.e. IL-4 and IL-5) and stromal cell-derived factor-1α in MLN cells compared to OVA exposure alone. These effects were more prominent with 0.0625 or 1.25 pmol/animal/week of BPA. Furthermore, exposure to OVA + BPA altered serum levels of anti-inflammatory corticosterone, estrogen receptor 2 messenger RNA (mRNA) expression in the lungs and spleen functionality. These findings suggest that low-dose BPA exposure may aggravate allergic airway inflammation by enhancing Th2 responses via disruption of the immune system.

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Long-Lasting Anti-Inflammatory and Antinociceptive Effects of Acute Ammonium Glycyrrhizinate Administration: Pharmacological, Biochemical, and Docking Studies

Molecules ◽

10.3390/molecules24132453 ◽

2019 ◽

Vol 24 (13) ◽

pp. 2453 ◽

Cited By ~ 6

Author(s):

Francesco Maione ◽

Paola Minosi ◽

Amalia Di Giannuario ◽

Federica Raucci ◽

Maria Giovanna Chini ◽

...

Keyword(s):

Animal Models ◽

Antinociceptive Effect ◽

Binding Pocket ◽

Docking Studies ◽

Prostaglandin E ◽

Single Administration ◽

Antinociceptive Effects ◽

Anti Inflammatory

The object of the study was to estimate the long-lasting effects induced by ammonium glycyrrhizinate (AG) after a single administration in mice using animal models of pain and inflammation together with biochemical and docking studies. A single intraperitoneal injection of AG was able to produce anti-inflammatory effects in zymosan-induced paw edema and peritonitis. Moreover, in several animal models of pain, such as the writhing test, the formalin test, and hyperalgesia induced by zymosan, AG administered 24 h before the tests was able to induce a strong antinociceptive effect. Molecular docking studies revealed that AG possesses higher affinity for microsomal prostaglandin E synthase type-2 compared to type-1, whereas it seems to locate better in the binding pocket of cyclooxygenase (COX)-2 compared to COX-1. These results demonstrated that AG induced anti-inflammatory and antinociceptive effects until 24–48 h after a single administration thanks to its ability to bind the COX/mPGEs pathway. Taken together, all these findings highlight the potential use of AG for clinical treatment of pain and/or inflammatory-related diseases.

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