An Integral Role for Heme Oxygenase-1 and Carbon Monoxide in Maintaining Peripheral Tolerance by CD4+CD25+ Regulatory T Cells

Brusko, Todd M.; Wasserfall, Clive; Agarwal, Anupam; Kapturczak, Matthias H.; Atkinson, Mark A.

doi:10.4049/jimmunol.174.9.5181

Cited by 114 publications

(71 citation statements)

References 77 publications

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“…IDO catalyzes the rate-limiting step of tryptophane degradation. Kynurenine, one of the products of this reaction, affects proliferation as well as differentiation of helper T cells (Brusko et al, 2005;Munn and Mellor, 2007). Likely, in an inflammatory environment the presence of AC might help to promote healing, once an inflammatory stimulus is eliminated, by modulating adaptive immune responses.…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

Weis

Weigert

Knethen

et al. 2009

MBoC

151

128

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Apoptotic cells (AC) are rapidly engulfed by professional phagocytes such as macrophages to avoid secondary necrosis and thus inflammation. Recognition of AC polarizes macrophages toward an anti-inflammatory phenotype, which shows homology to an alternatively activated M2 macrophage. However, mechanistic details provoking these phenotype alterations are incompletely understood. Here, we demonstrate a biphasic up-regulation of heme oxygenase-1 (HO-1), a protein that bears an antiapoptotic as well as an anti-inflammatory potential, in primary human macrophages, which were exposed to the supernatant of AC. Although the first phase of HO-1 induction at 6 h was accomplished by AC-derived sphingosine-1-phosphate (S1P) acting via S1P receptor 1, the second wave of HO-1 induction at 24 h was attributed to autocrine signaling of vascular endothelial growth factor A (VEGFA), whose expression and release were facilitated by S1P. Whereas VEGFA release from macrophages was signal transducer and activator of transcription (STAT) 1-dependent, vascular endothelial growth factor itself triggered STAT1/STAT3 heterodimer formation, which bound to and activated the HO-1 promoter. Knockdown of HO-1 proved its relevance in facilitating enhanced expression of the antiapoptotic proteins Bcl-2 and Bcl-X L , as well as the anti-inflammatory adenosine receptor A 2A . These findings suggest that HO-1, which is induced by AC-derived S1P, is critically involved in macrophage polarization toward an M2 phenotype.

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Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

Weis

Weigert

Knethen

et al. 2009

MBoC

151

128

View full text Add to dashboard Cite

show abstract

“…21 This has led to the proposal that HO-1 and CO may mediate immune tolerance by favoring the induction of master immunosuppressor cells, the so-called regulatory T cells (Tregs). 22,23 Therefore, the activation of HO-1 expression can be thought of as a critical parameter to switch the classical proinflammatory activity of macrophages into an immunoregulatory one. It remains to be determined whether, at high concentrations of intracellular heme, as encountered after transfusion of stored blood, the HO system becomes overwhelmed and therefore is unable to neutralize the oxidative and inflammatory effects.…”

Section: Heme and Heme Oxygenase Systemmentioning

confidence: 99%

Immunoregulatory Effects of Stored Red Blood Cells

2011

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Some clinical studies have identified potential adverse patient outcomes associated with RBC storage length. This may in part be due to the release of potentially hazardous bioactive products that accumulate during storage and are delivered at high concentrations during transfusion. In this situation, a proinflammatory tissue microenvironment may be established that can alter immunoregulatory mechanisms. This review highlights some of the potential immunomodulatory effects of stored RBCs that may be responsible for adverse transfusion reactions.

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“…64 Inhibition of neutrophil aggregation also may underlie the anti-inflammatory effects of CO. 65 CO also increases regulatory T cells, which inhibit the Thelper 1 (Th1) cytokine response. 66 Due to its potential toxicity, CO has not been trialled in human subjects.…”

Section: 21mentioning

confidence: 99%

Review article: ulcerative colitis, smoking and nicotine therapy

Lunney

Leong

2012

Aliment Pharmacol Ther

119

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SummaryBackgroundSmoking is the best‐characterised environmental association of ulcerative colitis (UC). Smoking has been observed to exert protective effects on both the development and progression of UC.AimsTo examine the association between UC and smoking, possible pathogenic mechanisms and the potential of nicotine as a therapeutic agent in the treatment of UC.MethodsA literature search was conducted through MEDLINE, using the MeSH search terms ‘ulcerative colitis’ and ‘smoking’ or ‘nicotine’. Relevant articles were identified through manual review. The reference lists of these articles were reviewed to include further appropriate articles.ResultsUlcerative colitis is less prevalent in smokers. Current smokers with a prior diagnosis of UC are more likely to exhibit milder disease than ex‐smokers and nonsmokers. There is conflicting evidence for smokers having reduced rates of hospitalisation, colectomy and need for oral corticosteroids and immunosuppressants to manage their disease. Multiple potential active mediators in smoke may be responsible for these clinical effects, including nicotine and carbon monoxide, but the precise mechanism remains unknown. Nicotine has demonstrated variable efficacy in the induction of remission in UC when compared to placebo and conventional medicines. Despite this, the high frequency of adverse events limits its clinical significance.ConclusionsNicotine's application as a therapeutic treatment in ulcerative colitis is limited. Presently, it may be an option considered only in selected cases of acute ulcerative colitis refractory to conventional treatment options. This review also questions whether nicotine is the active component of smoking that modifies risk and inflammation in ulcerative colitis.

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An Integral Role for Heme Oxygenase-1 and Carbon Monoxide in Maintaining Peripheral Tolerance by CD4+CD25+ Regulatory T Cells

Cited by 114 publications

References 77 publications

Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

Immunoregulatory Effects of Stored Red Blood Cells

Review article: ulcerative colitis, smoking and nicotine therapy

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