- Title
- GSTO1-1 is an upstream suppressor of M2 macrophage skewing and HIF-1α-induced eosinophilic airway inflammation
- Creator
- Sokulsky, Leon A.; Goggins, Bridie; Sherwin, Simonne; Eyers, Fiona; Kaiko, Gerard E.; Board, Philip G.; Keely, Simon; Yang, Ming; Foster, Paul S.
- Relation
- NHRMC.APP1120696 http://purl.org/au-research/grants/nhmrc/1120696
- Relation
- Clinical & Experimental Allergy Vol. 50, Issue 5, p. 609-624
- Publisher Link
- http://dx.doi.org/10.1111/cea.13582
- Publisher
- Wiley-Blackwell
- Resource Type
- journal article
- Date
- 2020
- Description
- 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.
- Subject
- asthma; chemokines; eosinophils; hypoxia; macrophages; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1436506
- Identifier
- uon:40046
- Identifier
- ISSN:0954-7894
- Language
- eng
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