TLR4 activation alters labile heme levels to regulate BACH1 and heme oxygenase-1 expression in macrophages

Sudan, Kritika; Vijayan, Vijith; Madyaningrana, Kukuh; Gueler, Faikah; Igarashi, Kazuhiko; Foresti, Roberta; Motterlini, Roberto; Immenschuh, Stephan

doi:10.1016/j.freeradbiomed.2019.04.024

Cited by 35 publications

(29 citation statements)

References 65 publications

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“…Accordingly, we have shown that the regulatory pattern of labile heme levels correlated with that of HO-1 in macrophages [26]. Specifically, in mouse macrophages, stimulation with the TLR4 ligand lipopolysaccharide up-regulated intracellular labile heme levels and HO-1, whereas in human macrophages, the same stimulus led to an opposing regulatory pattern [26]. Thus, we hypothesize that labile heme is an up-stream signal required for HO-1 regulation and may function via interaction with the heme-sensitive transcriptional factor (TF) BTB and CNC homologue (BACH1), which will be discussed in detail below.…”

Section: The Intra-and Extracellular Pool Of Labile Hemementioning

confidence: 76%

“…Independent studies have indicated the presence of labile heme in different cellular compartments such as the nucleus, mitochondria, cytosol, Golgi complex, and endoplasmic reticulum [23,25], leading to the notion that this heme fraction might have intracellular signaling functions. Accordingly, we have shown that the regulatory pattern of labile heme levels correlated with that of HO-1 in macrophages [26]. Specifically, in mouse macrophages, stimulation with the TLR4 ligand lipopolysaccharide up-regulated intracellular labile heme levels and HO-1, whereas in human macrophages, the same stimulus led to an opposing regulatory pattern [26].…”

Section: The Intra-and Extracellular Pool Of Labile Hemementioning

confidence: 92%

“…The intracellular labile heme pool might also be used for incorporation into high turnover proteins such as cyclooxygenase-2, NADPH oxidase-2, and inducible nitric oxide synthase (iNOS), all of which are up-regulated by pro-inflammatory stimuli in immune cells such as macrophages to mount an efficient inflammatory response. It is conceivable, that the labile heme pool is controlled via the enzymatic synthesis of heme in cellular steady-state because its inhibition either by succinylacetone or N-methyl protoporphyrin IX down-regulates intracellular heme levels [20,21,26]. Notably, labile heme does not seem to be degraded by up-regulation of the heme-degrading enzyme HO-1, which might be explained by the K m of HO-1 for heme (<1 µM) [27,28].…”

Section: The Intra-and Extracellular Pool Of Labile Hemementioning

confidence: 99%

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Interplay of Heme with Macrophages in Homeostasis and Inflammation

Pradhan

Vijayan

Gueler

et al. 2020

IJMS

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Macrophages are an integral part of the mononuclear phagocyte system that is critical for maintaining immune homeostasis. They play a key role for initiation and modulation of immunological responses in inflammation and infection. Moreover, macrophages exhibit a wide spectrum of tissue-specific phenotypes in steady-state and pathophysiological conditions. Recent clinical and experimental evidence indicates that the ubiquitous compound heme is a crucial regulator of these cells, e.g., in the differentiation of monocytes to tissue-resident macrophages and/ or in activation by inflammatory stimuli. Notably, heme, an iron containing tetrapyrrole, is essential as a prosthetic group of hemoproteins (e.g., hemoglobin and cytochromes), whereas non-protein bound free or labile heme can be harmful via pro-oxidant, pro-inflammatory, and cytotoxic effects. In this review, it will be discussed how the complex interplay of heme with macrophages regulates homeostasis and inflammation via modulating macrophage inflammatory characteristics and/ or hematopoiesis. A particular focus will be the distinct roles of intra- and extracellular labile heme and the regulation of its availability by heme-binding proteins. Finally, it will be addressed how heme modulates macrophage functions via specific transcriptional factors, in particular the nuclear repressor BTB and CNC homologue (BACH)1 and Spi-C.

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Section: The Intra-and Extracellular Pool Of Labile Hemementioning

confidence: 76%

Section: The Intra-and Extracellular Pool Of Labile Hemementioning

confidence: 92%

Section: The Intra-and Extracellular Pool Of Labile Hemementioning

confidence: 99%

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Interplay of Heme with Macrophages in Homeostasis and Inflammation

Pradhan

Vijayan

Gueler

et al. 2020

IJMS

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“…Thus, we proceeded to analyze the crosstalk between this pathway and heme biology by exploring the overlap between HemeKG and the TLR pathways in the three aforementioned databases. Although heme has been linked to numerous (TLRs) including TLR2, TLR3, TLR4, TLR7, and TLR9 (Figueiredo et al, 2007;Lin et al, 2010;Dutra and Bozza, 2014;Min et al, 2017;Merle et al, 2019;Sudan et al, 2019), our analysis was prioritized on the most well-documented interaction, the one between heme and TLR4. Heme stimulates TLR4 to activate NF-κB secretion via myeloid differentiation primary response 88 (MyD88)-mediated activation of lκB (IKK) (see below).…”

Section: Dissection Of the Crosstalk Between Heme And Tlr Using Hemekgmentioning

confidence: 99%

A Computational Approach for Mapping Heme Biology in the Context of Hemolytic Disorders

Humayun

Domingo‐Fernándéz

George

et al. 2020

Front. Bioeng. Biotechnol.

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Heme is an iron ion-containing molecule found within hemoproteins such as hemoglobin and cytochromes that participates in diverse biological processes. Although excessive heme has been implicated in several diseases including malaria, sepsis, ischemiareperfusion, and disseminated intravascular coagulation, little is known about its regulatory and signaling functions. Furthermore, the limited understanding of heme's role in regulatory and signaling functions is in part due to the lack of curated pathway resources for heme cell biology. Here, we present two resources aimed to exploit this unexplored information to model heme biology. The first resource is a terminology covering heme-specific terms not yet included in standard controlled vocabularies. Using this terminology, we curated and modeled the second resource, a mechanistic knowledge graph representing the heme's interactome based on a corpus of 46 scientific articles. Finally, we demonstrated the utility of these resources by investigating the role of heme in the Toll-like receptor signaling pathway. Our analysis proposed a series of crosstalk events that could explain the role of heme in activating the TLR4 signaling pathway. In summary, the presented work opens the door to the scientific community for exploring the published knowledge on heme biology.

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“…Labile heme assay was performed in 96 well plates as previously described (13,14) with minor adaptations for measurement in tissue samples. Immediately after sacrifice the kidney tissue samples were weighed and minced in 1 ml Hank's Balanced Salt solution (HBSS).…”

Section: Determination Of Labile Heme With An Apo-horseradish Peroxidmentioning

confidence: 99%

Labile Heme Aggravates Renal Inflammation and Complement Activation After Ischemia Reperfusion Injury

et al. 2019

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Background: Ischemia reperfusion injury (IRI) plays a major role in solid organ transplantation. The length of warm ischemia time is critical for the extent of tissue damage in renal IRI. In this experimental study we hypothesized that local release of labile heme in renal tissue is triggered by the duration of warm ischemia (15 vs. 45 min IRI) and mediates complement activation, cytokine release, and inflammation. Methods: To induce IRI, renal pedicle clamping was performed in male C57BL/6 mice for short (15 min) or prolonged (45 min) time periods. Two and 24 h after experimental ischemia tissue injury labile heme levels in the kidney were determined with an apo-horseradish peroxidase assay. Moreover, renal injury, cytokines, and C5a and C3a receptor (C5aR, C3aR) expression were determined by histology, immunohistochemistry and qPCR, respectively. In addition, in vitro studies stimulating bone marrow-derived macrophages with LPS and the combination of LPS and heme were performed and cytokine expression was measured. Results: Inflammation and local tissue injury correlated with the duration of warm ischemia time. Labile heme concentrations in renal tissue were significantly higher after prolonged (45 min) as compared to short (15 min) IRI. Notably, expression of the inducible heme-degrading enzyme heme oxygenase-1 (HO-1) was up-regulated in kidneys after prolonged, but not after short IRI. C5aR, the pro-inflammatory cytokines IL-6 and TNF-α as well as pERK were up-regulated after prolonged, but not after short ischemia times. Consecutively, neutrophil infiltration and up-regulation of pro-fibrotic cytokines such as CTGF and PAI were more pronounced in prolonged IRI in comparison to short IRI. In vitro stimulation of macrophages with LPS revealed that IL-6 expression was enhanced in the presence of heme. Finally, administration of the heme scavenger human serum albumin (HSA) reduced the expression of pro-inflammatory cytokines, C3a receptor and improved tubular function indicated by enhanced alpha 1 microglobulin (A1M) absorption after IRI. Conclusions: Our data show that prolonged duration of warm ischemia time increased labile heme levels in the kidney, which correlates with IRI-dependent inflammation and up-regulation of anaphylatoxin receptor expression.

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TLR4 activation alters labile heme levels to regulate BACH1 and heme oxygenase-1 expression in macrophages

Cited by 35 publications

References 65 publications

Interplay of Heme with Macrophages in Homeostasis and Inflammation

Interplay of Heme with Macrophages in Homeostasis and Inflammation

A Computational Approach for Mapping Heme Biology in the Context of Hemolytic Disorders

Labile Heme Aggravates Renal Inflammation and Complement Activation After Ischemia Reperfusion Injury

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