GSTO1-1 is an upstream suppressor of M2 macrophage skewing and HIF-1α-induced eosinophilic airway inflammation.

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 signaling 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.To determine the role of GSTO1-1 in regulating HDM-induced allergic inflammation in a preclinical model of asthma.Wild-type and GSTO1-1 deficient mice were sensitized and aeroallergen challenged with HDM to induce allergic inflammation and subsequently hallmark pathophysiological features characterized.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 upregulated. HIF-1α expression was found to be higher in the absence of GSTO1-1 and correlated with the upregulation 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.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.