Abstract
Allergic asthma is conventionally considered as a Th2 immune response characterized by eosinophilic inflammation. Recent investigations revealed that Th17 cells play an important role in the pathogenesis of non-eosinophilic asthma (NEA), resulting in steroid-resistant neutrophilic airway inflammation. Heme oxygenase-1 (HO-1) has anti-inflammation, anti-oxidation, and anti-apoptosis functions. However, its role in NEA is still unclear. Here, we explore the role of HO-1 in a mouse model of NEA. HO-1 inducer hemin or HO-1 inhibitor tin protoporphyrin IX was injected intraperitoneally into ovalbumin-challenged DO11.10 mice. Small interfering RNA (siRNA) was delivered into mice to knock down HO-1 expression. The results show that induction of HO-1 by hemin attenuated airway inflammation and decreased neutrophil infiltration in bronchial alveolar lavage fluid and was accompanied by a lower proportion of Th17 cells in mediastinal lymph nodes and spleen. More importantly, induction of HO-1 down-regulated Th17-related transcription factor retinoic acid-related orphan receptor γt (RORγt) expression and decreased IL-17A levels, all of which correlated with a decrease in phosphorylated STAT3 (p-STAT3) level and inhibition of Th17 cell differentiation. Consistently, the above events could be reversed by tin protoporphyrin IX. Also, HO-1 siRNA transfection abolished the effect of hemin induced HO-1 in vivo. Meanwhile, the hemin treatment promoted the level of Foxp3 expression and enhanced the proportion of regulatory T cells (Tregs). Collectively, our findings indicate that HO-1 exhibits anti-inflammatory activity in the mouse model of NEA via inhibition of the p-STAT3-RORγt pathway, regulating kinetics of RORγt and Foxp3 expression, thus providing a possible novel therapeutic target in asthmatic patients.
Highlights
Heme oxygenase-1 (HO-1) is an inducible enzyme that exerts multiple physiological functions
HO-1 Alleviates OVA-induced Neutrophilic Airway Inflammation in DO11.10 Mice—Previously, we found that up-regulation of HO-1 could protect against OVA-sensitized/challenged eosinophilic airway inflammation [16]
The results show that phosphorylated STAT3 (p-STAT3) level was decreased in CD4ϩ T cells from mice pretreated with hemin, but the level was only mildly reduced in CD4ϩ T cells after SnPP treatment with no statistical difference as compared with those from untreated mice
Summary
Heme oxygenase-1 (HO-1) is an inducible enzyme that exerts multiple physiological functions. Our findings indicate that HO-1 exhibits anti-inflammatory activity in the mouse model of NEA via inhibition of the p-STAT3-ROR␥t pathway, regulating kinetics of ROR␥t and Foxp expression, providing a possible novel therapeutic target in asthmatic patients. Recent studies using sputum induction and bronchial alveolar lavage (BAL) techniques indicate that ϳ50% of asthma is based on non-eosinophilic inflammation-involved polymorphonuclear neutrophils, mast cells, leukomonocytes, and macrophages [1,2,3]. These findings suggest that severe asthma may be a different subtype, namely non-eosinophilic asthma (NEA), rather than just an increase in asthma symptoms per se [4]. The current study sets out to examine the effect of HO-1 induction on Th17-mediated neutrophilic airway inflammation in DO11.10 T-cell receptor transgenic mice and investigate the mechanism by which HO-1 regulates Th17 immunity
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