GSTO1-1 is an upstream suppressor of M2 macrophage skewing and HIF-1α-induced eosinophilic airway inflammation.
Clin Exp Allergy
; 50(5): 609-624, 2020 05.
Article
en En
| MEDLINE
| ID: mdl-32052502
ABSTRACT
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-1ß 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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Asma
/
Proteínas Portadoras
/
Eosinófilos
/
Subunidad alfa del Factor 1 Inducible por Hipoxia
/
Glutatión Transferasa
/
Macrófagos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Clin Exp Allergy
Asunto de la revista:
ALERGIA E IMUNOLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Australia