A physiological model to study iron recycling in macrophages

Delaby, Constance; Pilard, Nathalie; Hetet, Gilles; Driss, Fathi; Grandchamp, Bernard; Beaumont, Carole; Canonne‐Hergaux, François

doi:10.1016/j.yexcr.2005.07.002

Cited by 93 publications

(104 citation statements)

References 45 publications

(60 reference statements)

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“…To evaluate the difference between physiologically aged and damaged RBC, surface PS was quantified with fluorescent annexin V on RBC treated with calcium and the calcium ionophore A23187, a treatment that induces PS externalization. 20 Much higher mean fluorescence was measured on ionophore-treated RBC than on non-treated RBC (76±21 and 29±13, respectively, n=3, P<0.05, Figure 5A). Control blood contained about 14% RBC that were more than 6 weeks old ( Figure 1D) and these sRBC exhibited high levels of externalized PS (Figure 2A).…”

Section: Senescent Red Blood Cells Are Phagocytosed By Macrophages Inmentioning

confidence: 89%

“…In addition, control RBC were treated with tert-butyl hydroperoxide as described elsewhere 30 or PS was externalized by treatment with calcium and the calciumionophore A23187 as also described previously. 20 Alternatively, y. gottlieb et al…”

Section: In Vitro Erythrophagocytosismentioning

confidence: 99%

“…Glutaraldehyde 10 or ribavirin 19 was used to damage the RBC morphology. 9 External exposure of PS was mostly induced by calcium and calciumionophore administration, 15,20 but was also detected after the addition of ribavirin, oxidizing agents, low levels of lead or prolonged incubation in phosphate-buffered saline (PBS). 21,22 The naturally occurring accumulation of antiband 3 antibodies on RBC membranes during aging was mimicked successfully by opsonization of RBC, which led to massive EPC.…”

Section: Introductionmentioning

confidence: 99%

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Physiologically aged red blood cells undergo erythrophagocytosis in vivo but not in vitro

Gottlieb¹,

Topaz²,

Cohen³

et al. 2012

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundThe lifespan of red blood cells is terminated when macrophages remove senescent red blood cells by erythrophagocytosis. This puts macrophages at the center of systemic iron recycling in addition to their functions in tissue remodeling and innate immunity. Thus far, erythrophagocytosis has been studied by evaluating phagocytosis of erythrocytes that were damaged to mimic senescence. These studies have demonstrated that acquisition of some specific individual senescence markers can trigger erythrophagocytosis by macrophages, but we hypothesized that the mechanism of erythrophagocytosis of such damaged erythrocytes might differ from erythrophagocytosis of physiologically aged erythrocytes. Design and MethodsTo test this hypothesis we generated an erythrocyte population highly enriched in senescent erythrocytes by a hypertransfusion procedure in mice. Various erythrocyte-aging signals were analyzed and erythrophagocytosis was evaluated in vivo and in vitro. ResultsThe large cohort of senescent erythrocytes from hypertransfused mice carried numerous aging signals identical to those of senescent erythrocytes from control mice. Phagocytosis of fluorescently-labeled erythrocytes from hypertransfused mice injected into untreated mice was much higher than phagocytosis of labeled erythrocytes from control mice. However, neither erythrocytes from hypertransfused mice, nor those from control mice were phagocytosed in vitro by primary macrophage cultures, even though these cultures were able to phagocytose oxidatively damaged erythrocytes. ConclusionsThe large senescent erythrocyte population found in hypertransfused mice mimics physiologically aged erythrocytes. For effective erythrophagocytosis of these senescent erythrocytes, macrophages depend on some features of the intact phagocytosing tissue for support. ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

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Section: Senescent Red Blood Cells Are Phagocytosed By Macrophages Inmentioning

confidence: 89%

Section: In Vitro Erythrophagocytosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Physiologically aged red blood cells undergo erythrophagocytosis in vivo but not in vitro

Gottlieb¹,

Topaz²,

Cohen³

et al. 2012

Haematologica

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“…Forbes and Gros (56) also concluded that Slc11a1 was a proton/divalent cation symporter, transporting divalent cations down a proton gradient. Importantly, none of the studies undertaken in mammalian cells to measure Slc11a1-mediated divalent cation transport has looked at the influence of experimental conditions on the expression of endogenous Slc11a2 isoforms, or other molecules such as hepcidin (59,60) and ferroportin 1 (61,62) that are known to be involved in regulating iron traffic at the phagosome and plasma membranes in macrophages. In studies looking at iron transport, in particular, changes in intracellular iron will feedback on expression of Slc11a2-IRE isoforms, hepcidin and ferroportin 1.…”

Section: Discussionmentioning

confidence: 99%

Evolution of Differences in Transport Function in Slc11a Family Members

Techau

Taubas

Popoff

et al. 2007

Journal of Biological Chemistry

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Slc11a1 (formerly Nramp1) is a proton/divalent cation transporter that regulates cation homeostasis in macrophages. Slc11a2 mediates divalent cation uptake via the gut and delivery into cells. The mode of action of the two transporters remains controversial. Heterologous expression in frog oocytes shows Slc11a2 is a symporter, whereas Slc11a1 is an antiporter fluxing divalent cations against the proton gradient. This explains why Slc11a2, but not Slc11a1, can complement EGTA sensitivity in smf1⌬/smf2⌬/smf3⌬ yeast. However, some studies of transport in mammalian cells suggest Slc11a1 is a symporter. We now demonstrate that Slc11a1, but not Slc11a2, complements a divalent cation stress phenotype in bsd2⌬/rer1⌬ yeast. This is the first description of a yeast complementation assay for Slc11a1 function. Given the prior demonstration in frog oocytes that Slc11a1 acts as an antiporter, the most plausible interpretation of the data is that Slc11a1 is rescuing bsd2⌬/rer1⌬ yeast by exporting divalent cations. Chimaeras define the N terminus, and a segment of the protein core preceding transmembrane domain 9 through transmembrane domain 12, as important in rescuing the divalent cation stress phenotype. EGTA sensitivity and divalent cation stress phenotypes in yeast expressing Slc11a orthologues show that symport activity is ancestral. Molecular changes that mediate rescue of the divalent cation stress phenotype post-date frogs and co-evolved with Slc11a1 orthologues that regulate divalent cation homeostasis in macrophages and resistance to infection in chickens and mammals.Slc11a1 (formerly Ity/Lsh/Bcg/Nramp1) is a proton/divalent cation transporter with 12 putative transmembrane domains (TMD) 4 (1) that localizes to late endosomes and lysosomes of macrophages (2, 3) and dendritic cells (4), and tertiary granules of neutrophils (5). It is recruited to phagosome membranes in macrophages infected with Mycobacterium (2, 3) or Leishmania (3), and regulates cellular divalent cation homeostasis (6, 7). Polymorphisms at murine Slc11a1 and human SLC11A1 contribute to susceptibility to numerous infectious and autoimmune diseases (8, 9). Slc11a2 (also Nramp2/DMT1/DCT1) shares 64% amino acid identity with Slc11a1 (10) and regulates divalent cation uptake via the gut and delivery of iron into multiple cell types (11,12). Different isoforms can be distinguished by different C-terminal amino acid sequences, and by the presence or absence of an iron response element located in the 3Ј-untranslated region of the mRNA (13). The IRE-containing isoform (Slc11a2-IRE) is expressed predominantly in epithelial cells and localizes to late endosome/lysosomes, whereas the non-IRE-containing isoform (Slc11a2-nonIRE) is expressed in blood cell lineages and localizes to early endosomes (13). Both isoforms localize to their respective endosomal compartments and to apical membranes when expressed in polarized MadinDarby canine kidney cells (13). Mutation at Slc11a2 in mice and rats is associated with microcytic anemia (14, 15).Fe 2ϩ , Zn 2ϩ , Mn 2ϩ , Co ...

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“…Overexpression of FPN1 increased the levels of iron released from M⌽ after erythrophagocytosis (90). Expression of both FPN1 and HO-1 was dramatically induced within 4 h after erythrophagocytosis in M⌽ (91,92). Whether heme is degraded within the phagolysosome or in the cytosol is unclear.…”

Section: Recycling Of Heme and Heme Ironmentioning

confidence: 99%

Iron and Porphyrin Trafficking in Heme Biogenesis

Schultz

Chen

Paw

et al. 2010

Journal of Biological Chemistry

123

107

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Iron is an essential element for diverse biological functions. In mammals, the majority of iron is enclosed within a single prosthetic group: heme. In metazoans, heme is synthesized via a highly conserved and coordinated pathway within the mitochondria. However, iron is acquired from the environment and subsequently assimilated into various cellular pathways, including heme synthesis. Both iron and heme are toxic but essential cofactors. How is iron transported from the extracellular milieu to the mitochondria? How are heme and heme intermediates coordinated with iron transport? Although recent studies have answered some questions, several pieces of this intriguing puzzle remain unsolved.

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A physiological model to study iron recycling in macrophages

Cited by 93 publications

References 45 publications

Physiologically aged red blood cells undergo erythrophagocytosis in vivo but not in vitro

Physiologically aged red blood cells undergo erythrophagocytosis in vivo but not in vitro

Evolution of Differences in Transport Function in Slc11a Family Members

Iron and Porphyrin Trafficking in Heme Biogenesis

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