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

Zhang, Yanjie; Zhang, Liya; Wu, Jinhong; Di, Caixia; Xia, Zhenwei

doi:10.1074/jbc.m113.494369

Cited by 58 publications

(50 citation statements)

References 60 publications

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“…The increased frequencies and enhanced suppressive activity of GARP + CD4 + CD25 + Tregs could effectively inhibit the hyperproliferation of Th1 cells to maintain immune homeostasis by direct cell-cell contact and the expression of anti-inflammatory cytokine TGF-β1. HO-1 has been shown to suppress Th17 cell-mediated immune response in some animal models [40,41]. Now, we further confirmed that HO-1 inhibited the Th17-dominant response in patients with ACS.…”

Section: Discussionsupporting

confidence: 80%

Heme Oxygenase-1 Restores Impaired GARP+CD4+CD25+ Regulatory T Cells from Patients with Acute Coronary Syndrome by Upregulating LAP and GARP Expression on Activated T Lymphocytes

Liu

Zhao

Zhong

et al. 2015

Cell Physiol Biochem

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Background: Accumulating evidence shows that the pathological autoreactive immune response is responsible for plaque rupture and the subsequent onset of acute coronary syndrome (ACS). Naturally occurring CD4⁺CD25⁺regulatory T cells (nTregs) are indispensable in suppressing the pathological autoreactive immune response and maintaining immune homeostasis. However, the number and the suppressive function of glycoprotein-A repetitions predominant (GARP) ⁺ CD4⁺ CD25⁺ activated nTregs were impaired in patients with ACS. Recent evidence suggests that heme oxygenase-1 (HO-1) can regulate the adaptive immune response by promoting the expression of Foxp3. We therefore hypothesized that HO-1 may enhance the function of GARP⁺ CD4⁺ CD25⁺Tregs in patients with ACS and thus regulate immune imbalance. Methods: T lymphocytes were isolated from healthy volunteers (control, n=30) and patients with stable angina (SA, n=40) or ACS (n=51). Half of these cells were treated with an HO-1 inducer (hemin) for 48 h, and the other half were incubated with complete RPMI-1640 medium. The frequencies of T-helper 1 (Th1), Th2, Th17 and latency-associated peptide (LAP) ⁺CD4⁺ T cells and the expression of Foxp3 and GARP by CD4⁺CD25⁺T cells were then assessed by measuring flow cytometry after stimulation in vitro. The suppressive function of activated Tregs was measured by thymidine uptake. The levels of transforming growth factor-1 (TGF-β1) in the plasma were measured using enzyme-linked immunosorbent assay (ELISA). The expression levels of the genes encoding these proteins were analyzed by real-time polymerase chain reaction. Results: Patients with ACS exhibited an impaired number and suppressive function of GARP⁺ CD4⁺ CD25⁺Tregs and a mixed Th1/Th17-dominant T cell response when compared with the SA and control groups. The expression of LAP in T cells was also lower in patients with ACS compared to patients with SA and the control individuals. Treatment with an HO-1 inducer enhanced the biological activity of GARP⁺ CD4⁺ CD25⁺Tregs and resulted in increased expression of LAP and GARP by activated T cells. Conclusions: The reduced number and impaired suppressive function of GARP⁺ CD4⁺ CD25⁺Tregs result in excess effector T cell proliferation, leading to plaque instability and the onset of ACS. HO-1 can effectively restore impaired GARP⁺ CD4⁺ CD25⁺Tregs from patients with ACS by promoting LAP and GARP expression on activated T cells.

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Section: Discussionsupporting

confidence: 80%

Heme Oxygenase-1 Restores Impaired GARP+CD4+CD25+ Regulatory T Cells from Patients with Acute Coronary Syndrome by Upregulating LAP and GARP Expression on Activated T Lymphocytes

Liu

Zhao

Zhong

et al. 2015

Cell Physiol Biochem

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“…Because HO-1 has pleiotropic immunomodulatory effects, there are already numerous illustrations of therapeutic applications of HO-1 in multiple experimental models of IBD mediated by various immune mechanisms (36 -38). Additionally, our previous studies have suggested that induction of HO-1 attenuates the airway inflammation in a mouse asthma model through promoting Tregs in eosinophilic airway inflammation (39,40) and inhibiting Th17 responses in non-eosinophilic airway inflammation (41). However, little is known about how HO-1 exerts immune regulatory effects under different inflammatory conditions.…”

Section: Inflammatory Bowel Disease (Ibd)mentioning

confidence: 99%

Heme Oxygenase-1 Ameliorates Dextran Sulfate Sodium-induced Acute Murine Colitis by Regulating Th17/Treg Cell Balance

Zhang

Zhong

et al. 2014

Journal of Biological Chemistry

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“…The regulation of HO-1 expression in macrophages was strictly required for protection against mycobacterial infection in mice, and HO-1-deficient mice were more susceptible to intravenous mycobacterium avium infections, and failed to mount a protective granulomatous response in mice lacking mature B cells (91). In a mouse model of noneosinophilic asthma, HO-1 provided anti-inflammatory effects by inhibiting the p-STAT3-RORct pathway (120). HO can also work along with the scaffold protein caveolin-1 and negatively regulate TLR-4 signaling.…”

Section: Ho-1 Reduces Inflammationmentioning

confidence: 99%

Heme Oxygenase in Neonatal Lung Injury and Repair

Dennery

2014

Antioxidants & Redox Signaling

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Significance: Premature and sick neonates are often exposed to high concentrations of oxygen, which results in lung injury and long-term adverse consequences. Nevertheless, neonates are more tolerant to hyperoxia than are adults. This may be, in part, explained by the high lung content of heme oxygenase-1 (HO-1), the rate-limiting enzyme in the degradation of heme and an important stress protein. The abundance of HO-1 dictates its cytoprotective and deleterious effects. Interestingly, in response to hyperoxia, lung HO-1 mRNA is not further up-regulated in neonates, suggesting that lung HO-1 gene expression is tightly regulated so as to optimize cytoprotection when faced with an oxidative stress such as hyperoxia. Recent Advances: In addition to the lack of induction of HO-1 mRNA, neonatal lung HO-1 protein is observed in the nucleus in neonatal mice exposed to hyperoxia but not in adults, which is further evidence for the developmental regulation of HO-1. Nuclear HO-1 had unique properties independent of its enzymatic activity. In addition, there has been increasing evidence that nuclear HO-1 contributes to cellular proliferation and malignant transformation in several human cancers. Critical Issues: Since HO-1 has dual effects in cytoprotection and cellular proliferation, the titration of HO-1 effects is critical to ensure beneficial actions against oxidative stress. Future Directions: Much more has to be understood about the specific roles of HO-1 so as to manipulate its abundance and/or nuclear migration to maximize the therapeutic benefit of this pleiotropic protein in the neonatal lung.

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

Cited by 58 publications

References 60 publications

Heme Oxygenase-1 Restores Impaired GARP+CD4+CD25+ Regulatory T Cells from Patients with Acute Coronary Syndrome by Upregulating LAP and GARP Expression on Activated T Lymphocytes

Heme Oxygenase-1 Restores Impaired GARP+CD4+CD25+ Regulatory T Cells from Patients with Acute Coronary Syndrome by Upregulating LAP and GARP Expression on Activated T Lymphocytes

Heme Oxygenase-1 Ameliorates Dextran Sulfate Sodium-induced Acute Murine Colitis by Regulating Th17/Treg Cell Balance

Heme Oxygenase in Neonatal Lung Injury and Repair

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