Heme Oxygenase-1 Exerts a Protective Role in Ovalbumin-induced Neutrophilic Airway Inflammation by Inhibiting Th17 Cell-mediated Immune Response

• Published in: The Journal of biological chemistry 2013-11, Vol.288 (48), p.34612-34626
• Main Authors: Zhang, Yanjie, Zhang, Liya, Wu, Jinhong, Di, Caixia, Xia, Zhenwei
• Format: Article
• Language: English
• Subjects: Animals; Asthma; Asthma - genetics; Asthma - pathology; Disease Models, Animal; Gene Expression Regulation; Heme Oxygenase; Heme Oxygenase-1 - antagonists & inhibitors; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Hemin - administration & dosage; Humans; Immunity, Innate; Immunology; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Interleukin-17 - metabolism; Lung - immunology; Lung - metabolism; Lung - pathology; Metalloporphyrins - administration & dosage; Mice; Neutrophils - metabolism; Neutrophils - pathology; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Protoporphyrins - administration & dosage; RNA, Small Interfering; STAT3 Transcription Factor - metabolism; T Cell; Th17; Th17 Cells - immunology; Th17 Cells - metabolism; Treg
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.494369

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. Background: Heme oxygenase-1 (HO-1) is an inducible enzyme that exerts multiple physiological functions. Results: Induction of HO-1 inhibits Th17-mediated neutrophilic airway inflammation in vivo and suppresses Th17 cell differentiation in vitro. Conclusion: HO-1 exhibits anti-inflammatory activity in non-eosinophilic asthma (NEA) by inhibiting Th17 responses. Significance: HO-1 may become a novel therapeutic target in NEA.