Heme Catabolic Pathway in Inflammation and Immune Disorders

Wu, Bing; Wu, Yan‐Chao; Tang, Wei

doi:10.3389/fphar.2019.00825

Cited by 68 publications

(53 citation statements)

References 208 publications

(265 reference statements)

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“…Haptoglobin (Hp), an acute phase protein, binds to hemoglobin and creates complexes which are subsequently taken up by hepatocytes and macrophages of the reticuloendothelial system via the CD163 receptor. Once binding capacity of Hp is saturated, free Hb is oxidized to methemoglobin and releases heme [15,16]. In spite of many important biological functions mentioned above, a free heme molecule embodies a threat and acts in a destructive way [15].…”

Section: Heme Functions and Its Catabolic Pathwaymentioning

confidence: 99%

“…Once binding capacity of Hp is saturated, free Hb is oxidized to methemoglobin and releases heme [15,16]. In spite of many important biological functions mentioned above, a free heme molecule embodies a threat and acts in a destructive way [15]. Due to its lipophilic properties, heme intercalates in the membranes and modifies cellular structures [17].…”

Section: Heme Functions and Its Catabolic Pathwaymentioning

confidence: 99%

“…Indeed, free heme in plasma is promptly scavenged and neutralized by hemopexin [21]. Afterward, heme-hemopexin complexes are cleared from circulation by hepatocytes and macrophages via the CD91 receptor and undergo lysosomal degradation [15,16,21].…”

Section: Heme Functions and Its Catabolic Pathwaymentioning

confidence: 99%

“…A free iron ion, which is released as one of the products of the reaction, is able to react with hydrogen peroxide and yield hydroxyl radicals; therefore, it can cause oxidative damage. However, it is noteworthy that induction of HO-1 is followed by upregulation of ferritin which binds free iron and neutralizes its cytotoxic effect [15].…”

Section: Heme Functions and Its Catabolic Pathwaymentioning

confidence: 99%

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Two Faces of Heme Catabolic Pathway in Newborns: A Potential Role of Bilirubin and Carbon Monoxide in Neonatal Inflammatory Diseases

Osiak

Wątroba²,

Kapka‐Skrzypczak

et al. 2020

Oxidative Medicine and Cellular Longevity

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In an infant’s body, all the systems undergo significant changes in order to adapt to the new, extrauterine environment and challenges which it poses. Fragile homeostasis can be easily disrupted as the defensive mechanisms are yet imperfect. The activity of antioxidant enzymes, i.e., superoxide dismutase, catalase, and glutathione peroxidase, is low; therefore, neonates are especially vulnerable to oxidative stress. Free radical burden significantly contributes to neonatal illnesses such as sepsis, retinopathy of premature, necrotizing enterocolitis, bronchopulmonary dysplasia, or leukomalacia. However, newborns have an important ally—an inducible heme oxygenase-1 (HO-1) which expression rises rapidly in response to stress stimuli. HO-1 activity leads to production of carbon monoxide (CO), free iron ion, and biliverdin; the latter is promptly reduced to bilirubin. Although CO and bilirubin used to be considered noxious by-products, new interesting properties of those compounds are being revealed. Bilirubin proved to be an efficient free radicals scavenger and modulator of immune responses. CO affects a vast range of processes such as vasodilatation, platelet aggregation, and inflammatory reactions. Recently, developed nanoparticles consisting of PEGylated bilirubin as well as several kinds of molecules releasing CO have been successfully tested on animal models of inflammatory diseases. This paper focuses on the role of heme metabolites and their potential utility in prevention and treatment of neonatal diseases.

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Section: Heme Functions and Its Catabolic Pathwaymentioning

confidence: 99%

Section: Heme Functions and Its Catabolic Pathwaymentioning

confidence: 99%

Section: Heme Functions and Its Catabolic Pathwaymentioning

confidence: 99%

Section: Heme Functions and Its Catabolic Pathwaymentioning

confidence: 99%

See 2 more Smart Citations

Two Faces of Heme Catabolic Pathway in Newborns: A Potential Role of Bilirubin and Carbon Monoxide in Neonatal Inflammatory Diseases

Osiak

Wątroba²,

Kapka‐Skrzypczak

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Heme catabolism is a well-known anti-inflammatory system in the context of infectious and autoimmune diseases [174,175]. The main effector of this pathway, heme oxygenase-1 (HMOX1) was found to interact with SARS-CoV-2 Orf3a, although the nature of this interaction remains ambiguous [34,176].…”

Section: Altered Host Metabolismmentioning

confidence: 99%

COVID-19 Disease Map, a computational knowledge repository of SARS-CoV-2 virus-host interaction mechanisms

Ostaszewski

Niarakis

Mazein

et al. 2020

Preprint

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We hereby describe a large-scale community effort to build an open-access, interoperable, and computable repository of COVID-19 molecular mechanisms - the COVID-19 Disease Map. We discuss the tools, platforms, and guidelines necessary for the distributed development of its contents by a multi-faceted community of biocurators, domain experts, bioinformaticians, and computational biologists. We highlight the role of relevant databases and text mining approaches in enrichment and validation of the curated mechanisms. We describe the contents of the map and their relevance to the molecular pathophysiology of COVID-19 and the analytical and computational modelling approaches that can be applied to the contents of the COVID-19 Disease Map for mechanistic data interpretation and predictions. We conclude by demonstrating concrete applications of our work through several use cases.

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NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions

Liu

Chen

Niu

et al. 2021

Clinical & Translational Med

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Background Blood transfusion, a common basic supporting therapy, can lead to acute hemolytic transfusion reaction (AHTR). AHTR poses a great risk to patients through kidney function damage in a short time. Previous reports found that heme from destroyed red blood cells impaired kidney function, and NLR family pyrin domain containing 3 (NLRP3) inflammasome was augmented in case of kidney injury. However, the detailed mechanism regarding whether NLRP3 inflammasome is involved in kidney function injury in AHTR is not fully understood yet. Methods Hemolysis models were established by vein injection with human blood plasma or mouse heme from destroyed red blood cells. The injured renal tubular epithelial cells (RTECs) were evaluated by tubular damage markers staining in hemolysis models and in primary RTECs in vitro. The activation of NLRP3 inflammasome in RTECs by hemes was investigated by Western blot, ELISA, scanning electron microscopy, immunofluorescent staining, flow cytometry, and hemolysis models. NLRP3 gene knockout mice were employed to confirm these observations in vitro and in vivo. The binding between a novel inhibitor (66PR) and NLRP3 was affirmed by molecule docking and co‐immunoprecipitation. The rescue of 66PR on kidney function impairment was explored in murine hemolysis models. Results We found that heme could activate NLRP3 inflammasome in RTECs to induce kidney function injury. NLRP3 gene knockout could prevent the damage of RTECs caused by hemes and recover kidney function in AHTR. Moreover, NLRP3 inflammasome chemical inhibitor, 66PR, could bind to NLRP3 protein and inhibit inflammasome activation in RTECs, which consequently relieved the injury of RTECs caused by hemes, and alleviated kidney function damage in the AHTR model. Conclusions Hemes could activate NLRP3 inflammasome in RTECs, and a novel NLRP3 inflammasome inhibitor named 66PR relieved kidney function damage in AHTR. Our findings provided a new possible strategy to treat kidney function failure in AHTR.

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Heme Catabolic Pathway in Inflammation and Immune Disorders

Cited by 68 publications

References 208 publications

Two Faces of Heme Catabolic Pathway in Newborns: A Potential Role of Bilirubin and Carbon Monoxide in Neonatal Inflammatory Diseases

Two Faces of Heme Catabolic Pathway in Newborns: A Potential Role of Bilirubin and Carbon Monoxide in Neonatal Inflammatory Diseases

COVID-19 Disease Map, a computational knowledge repository of SARS-CoV-2 virus-host interaction mechanisms

NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions

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