Heme modulates intestinal epithelial cell activation: involvement of NADPHox-derived ROS signaling

Barcellos-de-Souza, Pedro; Moraes, João Alfredo; de-Freitas-Junior, Júlio Cesar Madureira; Morgado‐Díaz, José Andrés; Barja‐Fidalgo, Christina; Arruda, Maria Augusta

doi:10.1152/ajpcell.00078.2012

Cited by 27 publications

(34 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, heme induces ROS generation dependent on enzymatic reactions. In fact, it was demonstrated that heme triggers ROS production by the NADPH oxidase enzyme (Graça-Souza et al, 2002; Arruda et al, 2004; Moraes et al, 2012; Barcellos-de-Souza et al, 2013) and by mitochondria (unpublished), through activation of specific signaling pathways (Graça-Souza et al, 2002; Porto et al, 2007; Fernandez et al, 2010; Fortes et al, 2012). Alternatively, heme-induced formation of radical species relies on the conversion of low-reactive organic hydroperoxides (ROOH) into highly reactive alkoxyl (RO•) and peroxyl (ROO•) radicals (Tappel, 1953, 1955; Van der Zee et al, 1996).…”

Section: Direct Cytotoxic Effects Of Hemementioning

confidence: 99%

Heme on innate immunity and inflammation

Dutra¹,

Bozza²

2014

Front. Pharmacol.

276

266

View full text Add to dashboard Cite

Heme is an essential molecule expressed ubiquitously all through our tissues. Heme plays major functions in cellular physiology and metabolism as the prosthetic group of diverse proteins. Once released from cells and from hemeproteins free heme causes oxidative damage and inflammation, thus acting as a prototypic damage-associated molecular pattern. In this context, free heme is a critical component of the pathological process of sterile and infectious hemolytic conditions including malaria, hemolytic anemias, ischemia-reperfusion, and hemorrhage. The plasma scavenger proteins hemopexin and albumin reduce heme toxicity and are responsible for transporting free heme to intracellular compartments where it is catabolized by heme-oxygenase enzymes. Upon hemolysis or severe cellular damage the serum capacity to scavenge heme may saturate and increase free heme to sufficient amounts to cause tissue damage in various organs. The mechanism by which heme causes reactive oxygen generation, activation of cells of the innate immune system and cell death are not fully understood. Although heme can directly promote lipid peroxidation by its iron atom, heme can also induce reactive oxygen species generation and production of inflammatory mediators through the activation of selective signaling pathways. Heme activates innate immune cells such as macrophages and neutrophils through activation of innate immune receptors. The importance of these events has been demonstrated in infectious and non-infectious diseases models. In this review, we will discuss the mechanisms behind heme-induced cytotoxicity and inflammation and the consequences of these events on different tissues and diseases.

show abstract

Section: Direct Cytotoxic Effects Of Hemementioning

confidence: 99%

Heme on innate immunity and inflammation

Dutra¹,

Bozza²

2014

Front. Pharmacol.

276

266

View full text Add to dashboard Cite

show abstract

“…Compelling evidence from the literature shows that many of the inflammatory and cytotoxic effects exerted by heme are mediated by ROS that can be generated by enzymatic as well as nonenzymatic reactions (9,17,27,28). As an important source of cellular stress, an excess of ROS also has been implicated as a trigger for protein aggregation (29,30).…”

Section: To Test Whether P62mentioning

confidence: 99%

“…In pathological conditions that result in hemolysis, rhabdomyolysis, or extensive cell damage, large amounts of hemeproteins are released, and under oxidative conditions, the heme moiety is released, further increasing oxidation and cellular stress (7,8). Recently, it was shown that heme can induce the generation of reactive oxygen species (ROS) through the activation of NADPH oxidase (9) or by the mitochondria (10), and that blocking these pro-oxidant effects protects the host from cell damage and tissue injury.…”

mentioning

confidence: 99%

Protein aggregation as a cellular response to oxidative stress induced by heme and iron

Vasconcellos

Dutra

Siqueira

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hemolytic diseases include a variety of conditions with diverse etiologies in which red blood cells are destroyed and large amounts of hemeproteins are released. Heme has been described as a potent proinflammatory molecule that is able to induce multiple innate immune responses, such as those triggered by TLR4 and the NLRP3 inflammasome, as well as necroptosis in macrophages. The mechanisms by which eukaryotic cells respond to the toxic effects induced by heme to maintain homeostasis are not fully understood, however. Here we describe a previously uncharacterized cellular response induced by heme: the formation of p62/SQTM1 aggregates containing ubiquitinated proteins in structures known as aggresome-like induced structures (ALIS). This action is part of a response driven by the transcription factor NRF2 to the excessive generation of reactive oxygen species induced by heme that results in the expression of genes involved in antioxidant responses, including p62/SQTM1. Furthermore, we show that heme degradation by HO-1 is required for ALIS formation, and that the free iron released on heme degradation is necessary and sufficient to induce ALIS. Moreover, ferritin, a key protein in iron metabolism, prevents excessive ALIS formation. Finally, in vivo, hemolysis promotes an increase in ALIS formation in target tissues. Our data unravel a poorly understood aspect of the cellular responses induced by heme that can be explored to better understand the effects of free heme and free iron during hemolytic diseases such as sickle cell disease, dengue fever, malaria, and sepsis.autophagy | p62/SQSTM1 | ALIS | heme | iron

show abstract

“…ROS generated by heme has been mainly attributed to the Fenton reaction. However, recent studies suggest that heme can generate ROS through multiple sources, including NADPH oxidase and mitochondria (22,(24)(25)(26)(27).…”

mentioning

confidence: 99%

Hemolysis-induced lethality involves inflammasome activation by heme

Dutra

Alves

Rodrigues

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

287

281

View full text Add to dashboard Cite

Significance Heme causes inflammation in sterile and infectious conditions, contributing to the pathogenesis of sickle cell disease, malaria, and sepsis, but the mechanisms by which heme operates are not completely understood. Here we show that heme induces IL-1β processing through the activation of the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome in macrophages. Our results suggest that among NLRP3 activators, heme has common as well as unique requirements to trigger inflammasome activation. In vivo, hemolysis and heme cause inflammasome activation. Importantly, macrophages, inflammasome components, and IL-1R contribute to hemolysis-induced lethality. These results highlight the potential of understanding the molecular mechanisms by which heme is sensed by innate immune receptors as a way to identify new therapeutic strategies to treat the pathological consequences of hemolytic diseases.

show abstract

Heme modulates intestinal epithelial cell activation: involvement of NADPHox-derived ROS signaling

Abstract: Barcellos-De-Souza P, Moraes JA, de-Freitas-Junior JC, MorgadoDíaz JA, Barja-Fidalgo C, Arruda MA. Heme modulates intestinal epithelial cell activation: involvement of NADPHox-derived ROS signaling. Am

Cited by 27 publications

References 37 publications

Heme on innate immunity and inflammation

Heme on innate immunity and inflammation

Protein aggregation as a cellular response to oxidative stress induced by heme and iron

Hemolysis-induced lethality involves inflammasome activation by heme

Contact Info

Product

Resources

About