Immune Modulation by Inhibitors of the HO System

Fernández-Fierro, Ayleen; Funes, Samanta C.; Ríos, Mariana; Covián, Camila; González, Jorge; Kalergis, Alexis M.

doi:10.3390/ijms22010294

Cited by 27 publications

(22 citation statements)

References 156 publications

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“…Indeed, T cells constitutively express HO-1, and their expansion regulatory is positively influenced by a tolerogenic phenotype sustained through HO-1 induction in dendritic cells. HO-1 modulation or application of low concentrations of CO to LPS-challenged macrophages reduced TNF-α and IL-1β expression and simultaneously stimulated the anti-inflammatory IL-10 production through p38-MAPK activity [ 44 , 45 , 46 ].…”

Section: Resultsmentioning

confidence: 99%

A Novel Class of Dual-Acting DCH-CORMs Counteracts Oxidative Stress-Induced Inflammation in Human Primary Tenocytes

et al. 2021

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Carbon monoxide (CO) can prevent cell and tissue damage by restoring redox homeostasis and counteracting inflammation. CO-releasing molecules (CORMs) can release a controlled amount of CO to cells and are emerging as a safer therapeutic alternative to delivery of CO in vivo. Sustained oxidative stress and inflammation can cause chronic pain and disability in tendon-related diseases, whose therapeutic management is still a challenge. In this light, we developed three small subsets of 1,5-diarylpyrrole and pyrazole dicobalt(0)hexacarbonyl (DCH)-CORMs to assess their potential use in musculoskeletal diseases. A myoglobin-based spectrophotometric assay showed that these CORMs act as slow and efficient CO-releasers. Five selected compounds were then tested on human primary-derived tenocytes before and after hydrogen peroxide stimulation to assess their efficacy in restoring cell redox homeostasis and counteracting inflammation in terms of PGE2 secretion. The obtained results showed an improvement in tendon homeostasis and a cytoprotective effect, reflecting their activity as CO-releasers, and a reduction of PGE2 secretion. As these compounds contain structural fragments of COX-2 selective inhibitors, we hypothesized that such a composite mechanism of action results from the combination of CO-release and COX-2 inhibition and that these compounds might have a potential role as dual-acting therapeutic agents in tendon-derived diseases.

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Section: Resultsmentioning

confidence: 99%

A Novel Class of Dual-Acting DCH-CORMs Counteracts Oxidative Stress-Induced Inflammation in Human Primary Tenocytes

et al. 2021

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“…SnPP is a metalloporphyrin that acts as a competitive inhibitor of HO-1 both in vitro and in vivo. Its efficiency can be explained by its higher binding affinity to HO-1/2 than to heme [ 43 , 44 ]. However, enzymatically inactive HO-1 can still mediate protection against hydrogen peroxide-induced toxicity, probably by promoting the gene expression of antioxidant proteins [ 14 , 45 ], although the mechanisms underlying these effects are still unclear.…”

Section: Discussionmentioning

confidence: 99%

Heme-Oxygenase-1 Attenuates Oxidative Functions of Antigen Presenting Cells and Promotes Regulatory T Cell Differentiation during Fasciola hepatica Infection

Costa

Frigerio

et al. 2021

Antioxidants

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Fasciola hepatica is a fluke that infects livestock and humans causing fasciolosis, a zoonotic disease of increasing importance due to its worldwide distribution and high economic losses. The parasite regulates the host immune system by inducing a strong Th2 and regulatory T (Treg) cell immune response through mechanisms that might involve the expression or activity of heme-oxygenase-1 (HO-1), the rate-limiting enzyme in the catabolism of free heme that also has immunoregulatory and antioxidant properties. In this paper, we show that F. hepatica-infected mice upregulate HO-1 on peritoneal antigen-presenting cells (APC), which produce decreased levels of both reactive oxygen and nitrogen species (ROS/RNS). The presence of these cells was associated with increased levels of regulatory T cells (Tregs). Blocking the IL-10 receptor (IL-10R) during parasite infection demonstrated that the presence of splenic Tregs and peritoneal APC expressing HO-1 were both dependent on IL-10 activity. Furthermore, IL-10R neutralization as well as pharmacological treatment with the HO-1 inhibitor SnPP protected mice from parasite infection and allowed peritoneal APC to produce significantly higher ROS/RNS levels than those detected in cells from infected control mice. Finally, parasite infection carried out in gp91phox knockout mice with inactive NADPH oxidase was associated with decreased levels of peritoneal HO-1+ cells and splenic Tregs, and partially protected mice from the hepatic damage induced by the parasite, revealing the complexity of the molecular mechanisms involving ROS production that participate in the complex pathology induced by this helminth. Altogether, these results contribute to the elucidation of the immunoregulatory and antioxidant role of HO-1 induced by F. hepatica in the host, providing alternative checkpoints that might control fasciolosis.

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“…Both SnPPIX and ZnPPIX have been shown to strongly inhibit heme degradation. However, SnPPIX was found to be the most potent inhibitor of HO activity [ 58 ]. A list of modulators of HO-1 biosynthesis and inhibitors of the enzymatic activity of HO-1 are represented in Table 1 .…”

Section: Heme Oxygenase-1mentioning

confidence: 99%

Heme Oxygenase-1 as Therapeutic Target for Diabetic Foot Ulcers

Leal

Carvalho

2022

IJMS

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A diabetic foot ulcer (DFU) is one of the major complications of diabetes. Wound healing under diabetic conditions is often impaired. This is in part due to the excessive oxidative stress, prolonged inflammation, immune cell dysfunction, delayed re-epithelialization, and decreased angiogenesis present at the wound site. As a result of these multifactorial impaired healing pathways, it has been difficult to develop effective therapeutic strategies for DFU. Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in heme degradation generating carbon monoxide (CO), biliverdin (BV) which is converted into bilirubin (BR), and iron. HO-1 is a potent antioxidant. It can act as an anti-inflammatory, proliferative, angiogenic and cytoprotective enzyme. Due to its biological functions, HO-1 plays a very important role in wound healing, in part mediated through the biologically active end products generated by its enzymatic activity, particularly CO, BV, and BR. Therapeutic strategies involving the activation of HO-1, or the topical application of its biologically active end products are important in diabetic wound healing. Therefore, HO-1 is an attractive therapeutic target for DFU treatment. This review will provide an overview and discussion of the importance of HO-1 as a therapeutic target for diabetic wound healing.

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Immune Modulation by Inhibitors of the HO System

Cited by 27 publications

References 156 publications

A Novel Class of Dual-Acting DCH-CORMs Counteracts Oxidative Stress-Induced Inflammation in Human Primary Tenocytes

A Novel Class of Dual-Acting DCH-CORMs Counteracts Oxidative Stress-Induced Inflammation in Human Primary Tenocytes

Heme-Oxygenase-1 Attenuates Oxidative Functions of Antigen Presenting Cells and Promotes Regulatory T Cell Differentiation during Fasciola hepatica Infection

Heme Oxygenase-1 as Therapeutic Target for Diabetic Foot Ulcers

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