Control of iron homeostasis as a key component of macrophage polarization

Cairo, Gaetano; Locati, Massimo; Mantovani, Alberto

doi:10.3324/haematol.2010.030239

Cited by 45 publications

(41 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among the differential markers, macrophage polarization dictates iron handling by "inflammatory" and "alternatively active" macrophages, the latter showing larger intracellular labile iron deposits in association with high CD163 expression [20]. The presence of intracellular iron deposits has been documented in the foamy macrophages present in atherosclerotic lesions also in conjunction with high CD163 expression [21].…”

Section: Introductionmentioning

confidence: 99%

CD163 favors Mycobacterium leprae survival and persistence by promoting anti‐inflammatory pathways in lepromatous macrophages

et al. 2012

View full text Add to dashboard Cite

Lepromatous macrophages possess a regulatory phenotype that contributes to the immunosuppression observed in leprosy. CD163, a scavenger receptor that recognizes hemoglobin-haptoglobin complexes, is expressed at higher levels in lepromatous cells, although its functional role in leprosy is not yet established. We herein demonstrate that human lepromatous lesions are microenvironments rich in IDO + CD163 + . Cells isolated from these lesions were CD68 + IDO + CD163 + while higher levels of sCD163 in lepromatous sera positively correlated with IL-10 levels and IDO activity. Different Mycobacterium leprae (ML) concentrations in healthy monocytes likewise revealed a positive correlation between increased concentrations of the mycobacteria and IDO, CD209, and CD163 expression. The regulatory phenotype in ML-stimulated monocytes was accompanied by increased TNF, IL-10, and TGF-β levels whereas IL-10 blockade reduced ML-induced CD163 expression. The CD163 blockade reduced ML uptake in human monocytes. ML uptake was higher in HEK293 cells transfected with the cDNA for CD163 than in untransfected cells. Simultaneously, increased CD163 expression in lepromatous cells seemed to be dependent on ML uptake, and contributed to augmented iron storage in lepromatous macrophages. Altogether, these results suggest that ML-induced CD163 expression modulates the host cell phenotype to create a favorable environment for mycobacterial entry and survival.Keywords: CD163 r IL-10 r Leprosy r Macrophages IntroductionLeprosy is an infectious disease caused by Mycobacterium leprae (ML) in which susceptibility to the mycobacteria and its clinicalmanifestations are attributed to the host immune response. The clinical and immunological patterns of this unique chronic infectious disease clearly demonstrate a continuous scale of changes in histological lesions. Disease classification is defined Correspondence: Dr. Euzenir N. Sarno e-mail: euzenir@fiocruz.br within two poles (tuberculoid to lepromatous) with transitions between these clinical forms. While typical epithelioid macrophages predominate at the paucibacillary tuberculoid pole of the disease, inactivated foamy macrophages predominate at the lepromatous end [1]. In lepromatous leprosy (LL), the lack of systemic inflammatory signals and corresponding local ones strongly indicates that a complex anti-inflammatory network is at work. In this * These authors contributed equally to this work as first authors. * * These authors contributed equally to this work as senior authors. Eur. J. Immunol. 2012. 42: 2925-2936 regard, neuroendocrine system involvement, in conjunction with the existence of multiple suppressive pathways under the control of the innate and adaptive immune response, has been reported [2][3][4][5][6][7].We have suggested that IDO may play a role in a hitherto unknown suppressive mechanism in leprosy [6]. It has also been reported that accumulated oxidized host phospholipids in lepromatous macrophages downregulate the innate immune response [8]. Foamy macrophages seem to sust...

show abstract

Section: Introductionmentioning

confidence: 99%

CD163 favors Mycobacterium leprae survival and persistence by promoting anti‐inflammatory pathways in lepromatous macrophages

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Hepcidin-mediated Fpn down-regulation has been reported to result in iron accumulation in M1 macrophages, which may contribute to wound healing or chronic inflammation (Recalcati et al 2012). By contrast, immunosuppressive M2 macrophages resolve inflammation and promote parasite killing, angiogenesis, wound healing, matrix remodeling, and tumor growth by increasing the availability of extracellular iron and polarized Th2 responses (Brunelli & Rovere-Querini 2008, Corna et al 2010, Gaetano et al 2010, Recalcati et al 2010 The inflammatory peritoneal environment characterizes macrophage polarization toward the M2 phenotype expressing markers of alternative activation, particularly high levels of scavenger receptors, CD163 and CD206, which are involved in the export of hemederived iron and removal of inflammatory mediators respectively (Smith et al 2012, Capobianco & RovereQuerini 2013. Impaired ability of peritoneal macrophages to dispose apoptotic endometrial remnants and defective scavenging heme-bound iron, resulting from cyclic progesterone withdrawal, may activate macrophages recruited at sites of local hypoxia and tissue stress (Capobianco & Rovere-Querini 2013).…”

Section: Iron-induced Peritoneal Os In Endometriosis Developmentmentioning

confidence: 99%

“…The iron retention-prone M1 macrophages are characterized by up-regulated iron storage ferritin (FtH) that is accompanied by the down-regulation of transferrin receptor 1 (TfR1) and iron exporter ferroportin (Fpn) due to decreased activity of the iron regulatory protein 2 (IREB2 (IRP2)), a primary regulator of iron homeostasis within the cell, which in turn limits the labile iron pool (LIP) to protect themselves from oxidative damage (Corna et al 2010, Recalcati et al 2010. These cells perform several effector functions, including bacteriostatic activity, secretion of pro-inflammatory cytokines, immunostimulation, and tumor suppression, by inducing a polarized Th1 response (Gaetano et al 2010, Recalcati et al 2012. Hepcidin-mediated Fpn down-regulation has been reported to result in iron accumulation in M1 macrophages, which may contribute to wound healing or chronic inflammation (Recalcati et al 2012).…”

Section: Iron-induced Peritoneal Os In Endometriosis Developmentmentioning

confidence: 99%

Role of iron overload-induced macrophage apoptosis in the pathogenesis of peritoneal endometriosis

Pirdel¹,

Pirdel²

2014

Reproduction

View full text Add to dashboard Cite

This article presents an overview of the involvement of iron overload-induced nitric oxide (NO) overproduction in apoptosis of peritoneal macrophages of women with endometriosis. We have postulated that the peritoneal iron overload originated from retrograde menstruation or bleeding lesions in the ectopic endometrium, which may contribute to the development of endometriosis by a wide range of mechanisms, including oxidative damage and chronic inflammation. Excessive NO production may also be associated with impaired clearance of endometrial cells by macrophages, which promotes cell growth in the peritoneal cavity. Therefore, further research of the mechanisms and consequences of macrophage apoptosis in endometriosis helps discover novel therapeutic strategies that are designed to prevent progression of endometriosis.

show abstract

“…Other factors that influence the development of the erythrophagocytic phenotype include inflammatory cytokines. Murine and human macrophages treated with interferon-γ (M1 polarization) express lower levels of ferroportin and HO-1 than macrophages treated with IL-4/IL-13 (M2 phenotype), and the latter have a greater capacity for iron export [30,31]. In concert with their scavenging and tissue repair phenotype, M2 macrophages also take up heme-hemopexin and hemoglobin-haptoglobin complexes, using CD163 and CD91 receptors, respectively, both of which are highly expressed under M2 conditions (fig.…”

Section: Specialization Of Macrophages For Erythrophagocytosismentioning

confidence: 99%

Macrophages and Systemic Iron Homeostasis

2012

View full text Add to dashboard Cite

As a principal aspect of their scavenging function, splenic and hepatic macrophages phagocytize and degrade senescent and damaged erythrocytes to recover iron, mainly for the production of hemoglobin in new erythrocytes but also for other carriers and enzymes requiring iron. Splenic red pulp macrophages are specialized for iron recycling with increased expression of proteins for the uptake of hemoglobin, breakdown of heme and the export of iron. In humans, recycling macrophages contribute the majority of the iron flux into extracellular fluid, exceeding the contribution of dietary iron absorption and release of stored iron from hepatocytes. Iron release from macrophages is closely regulated by the interaction of hepcidin, a peptide hormone produced by hepatocytes, with the macrophage iron exporter ferroportin. In addition to their homeostatic role, macrophages employ multiple mechanisms to contain microbial infections by depriving microbes of iron. This review discusses the iron-scavenging function of macrophages in the context of iron homeostasis and host defense.

show abstract

Control of iron homeostasis as a key component of macrophage polarization

Cited by 45 publications

References 19 publications

CD163 favors Mycobacterium leprae survival and persistence by promoting anti‐inflammatory pathways in lepromatous macrophages

CD163 favors Mycobacterium leprae survival and persistence by promoting anti‐inflammatory pathways in lepromatous macrophages

Role of iron overload-induced macrophage apoptosis in the pathogenesis of peritoneal endometriosis

Macrophages and Systemic Iron Homeostasis

Contact Info

Product

Resources

About