GSTO1‐1 is an upstream suppressor of M2 macrophage skewing and HIF‐1α‐induced eosinophilic airway inflammation
| Autor: | Leon A. Sokulsky, Simon Keely, Philip G. Board, Paul S. Foster, Ming Yang, Simonne Sherwin, Gerard E. Kaiko, Fiona Eyers, Bridie J. Goggins |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Eotaxin Chemokine Immunology medicine.disease_cause Allergic inflammation Mice Animals Immunology and Allergy Medicine Glutathione Transferase Mice Knockout House dust mite Innate immune system biology business.industry Macrophages Aeroallergen Hypoxia-Inducible Factor 1 alpha Subunit biology.organism_classification M2 Macrophage Asthma Eosinophils biology.protein TLR4 Carrier Proteins business |
| Zdroj: | Clinical & Experimental Allergy. 50:609-624 |
| ISSN: | 1365-2222 0954-7894 |
| Popis: | BACKGROUND Glutathione S-transferases omega class 1 (GSTO1-1) is a unique member of the GST family regulating cellular redox metabolism and innate immunity through the promotion of LPS/TLR4/NLRP3 signalling in macrophages. House dust mite (HDM) triggers asthma by promoting type 2 responses and allergic inflammation via the TLR4 pathway. Although linked to asthma, the role of GSTO1-1 in facilitating type 2 responses and/or HDM-driven allergic inflammation is unknown. OBJECTIVE To determine the role of GSTO1-1 in regulating HDM-induced allergic inflammation in a preclinical model of asthma. METHODS Wild-type and GSTO1-1-deficient mice were sensitized and aeroallergen challenged with HDM to induce allergic inflammation and subsequently hallmark pathophysiological features characterized. RESULTS By contrast to HDM-challenged WT mice, exposed GSTO1-1-deficient mice had increased numbers of eosinophils and macrophages and elevated levels of eotaxin-1 and -2 in their lungs. M1 macrophage-associated factors, such as IL-1β and IL-6, were decreased in GSTO1-1-deficient mice. Conversely, M2 macrophage factors such as Arg-1 and Ym1 were up-regulated. HIF-1α expression was found to be higher in the absence of GSTO1-1 and correlated with the up-regulation of M2 macrophage markers. Furthermore, HIF-1α was shown to bind and activate the eotaxin-2 promotor. Hypoxic conditions induced significant increases in the levels of eotaxin-1 and -2 in GSTO1-deficient BMDMs, providing a potential link between inflammation-induced hypoxia and the regulation of M2 responses in the lung. Collectively, our results suggest that GSTO1-1 deficiency promotes M2-type responses and increased levels of nuclear HIF-1α, which regulates eotaxin (s)-induced eosinophilia and increased disease severity. CONCLUSION & CLINICAL IMPLICATION We propose that GSTO1-1 is a novel negative regulator of TLR4-regulated M2 responses acting as an anti-inflammatory pathway. The discovery of a novel HIF-1α-induced eotaxin pathway identifies an unknown connection between hypoxia and the regulation of the severity of allergic inflammation in asthma. |
| Databáze: | OpenAIRE |
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