Heme oxygenase-1 alleviates eosinophilic inflammation by inhibiting STAT3-SOCS3 signaling
- 1 June 2020
- journal article
- research article
- Published by Wiley in Pediatric Pulmonology
- Vol. 55 (6), 1440-1447
- https://doi.org/10.1002/ppul.24759
Abstract
Airway inflammation of eosinophilic asthma (EA) attributes to Th2 response, leaving the role of Th17 response unknown. Signal transducer and activator of transcription 3 (STAT3) induce both suppressors of cytokine signaling 3 (SOCS3) and retinoic acid receptor-related orphan nuclear receptor gamma (ROR gamma t) to initiate Th17 cell differentiation which is inhibited by SOCS3, a negative feedback regulator of STAT3. Heme oxygenase-1 (HO-1) is a stress-responsive, cytoprotective, and immunoregulatory molecular. Two other isoforms of the enzyme includes HO-2 and HO-3. Because HO-2 does not exhibit stress-related upregulation and distributes mainly in nervous system and HO-3 shows a low enzymatic activity, we tested a hypothesized anti-inflammatory role for HO-1 in EA by inhibiting STAT3-SOCS3 signaling. Animal model was established with Ovalbumin in wild type Balb/C mice. Hemin or SNPP was intraperitoneally (IP) injected ahead of the animal model to induce or inhibit HO-1 expression. Airway inflammation was evaluated by bronchoalveolar lavage, hematoxyline and eosin staining, enzyme-linked immunosorbent assay, and Western blot analysis. In vivo results showed that HO-1 induction inhibited phosphorylation of STAT3 and expression of SOCS3 and ROR gamma t, decreased Th2 and Th17 immune responses, and alleviated airway inflammation. In vitro results revealed that HO-1 inhibited phosphorylation of STAT3 and expression of SOCS3 in naive CD4(+) T cells. These findings identify HO-1 induction as a potential therapeutic strategy for EA treatment by reducing STAT3 phosphorylation, STAT3-SOCS3-mediated Th2/Th17 immune responses, and ultimate allergic airway inflammation.Keywords
Funding Information
- Natural Science Foundation of Fujian Province (2019J01580)
- National Natural Science Foundation of China (81900015)
This publication has 58 references indexed in Scilit:
- STAT6‐dependent and ‐independent mechanisms in Th2 polarizationEuropean Journal of Immunology, 2012
- IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contractionNature Medicine, 2012
- The many faces of Th17 cellsCurrent Opinion in Immunology, 2011
- Randomized Trial of Omalizumab (Anti-IgE) for Asthma in Inner-City ChildrenThe New England Journal of Medicine, 2011
- IL-2 and IL-4 Stimulate MEK1 Expression and Contribute to T Cell Resistance against Suppression by TGF-β and IL-10 in AsthmaThe Journal of Immunology, 2010
- A novel subset of CD4+ TH2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthmaThe Journal of Experimental Medicine, 2010
- IFNγ-dependent SOCS3 expression inhibits IL-6-induced STAT3 phosphorylation and differentially affects IL-6 mediated transcriptional responses in endothelial cellsAmerican Journal of Physiology-Cell Physiology, 2010
- IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cellsProceedings of the National Academy of Sciences of the United States of America, 2009
- Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor–β1The Journal of Experimental Medicine, 2006
- What does Stat3 do?JCI Insight, 2002