SLC11A1 (formerly NRAMP1) and disease resistance. Microreview

Blackwell, Jenefer M.; Goswami, Tapasree; Evans, Carlton A.; Sibthorpe, Dean; Papo, N.; White, Jacqueline K.; Searle, Susana; Miller, E.N.; Peacock, Christopher; Mohammed, Hussein Ali; Ibrahim, Muntaser E.

doi:10.1046/j.1462-5822.2001.00150.x

Cited by 218 publications

(163 citation statements)

References 96 publications

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“…Phagocytic cells generate reactive oxygen species (ROS) by the enzyme NADPH oxidase or Phox triggering a respiratory burst [33]. Macrophages also sequester and actively pump iron into late endosomes and phagolysosomes where additional ROS are generated in order to kill phagocytosed microorganisms [34]. Phagocytosis of inert particulates, including ultrafine air pollutants, has also been shown to trigger the respiratory burst in lung macrophage [15].…”

Section: 24mentioning

confidence: 99%

Targeted removal of bioavailable metal as a detoxification strategy for carbon nanotubes

Liu

Guo

Morris

et al. 2008

Carbon

124

110

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There is substantial evidence for toxicity and/or carcinogenicity upon inhalation of pure transition metals in fine particulate form. Carbon nanotube catalyst residues may trigger similar metal-mediated toxicity, but only if the metal is bioavailable and not fully encapsulated within fluid-protective carbon shells. Recent studies have documented the presence of bioavailable iron and nickel in a variety of commercial as-produced and vendor "purified" nanotubes, and the present article examines techniques to avoid or remove this bioavailable metal. First, data are presented on the mechanisms potentially responsible for free metal in "purified" samples, including kinetic limitations during metal dissolution, the re-deposition or adsorption of metal on nanotube outer surfaces, and carbon shell damage during last-step oxidation or one-pot purification. Optimized acid treatment protocols are presented for targeting the free metal, considering the effects of acid strength, composition, time, and conditions for post-treatment water washing. Finally, after optimized acid treatment, it is shown that the remaining, non-bioavailable (encapsulated) metal persists in a stable and biologically unavailable form up to two months in an in vitro biopersistence assay, suggesting that simple removal of bioavailable (free) metal is a promising strategy for reducing nanotube health risks.

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Section: 24mentioning

confidence: 99%

Targeted removal of bioavailable metal as a detoxification strategy for carbon nanotubes

Liu

Guo

Morris

et al. 2008

Carbon

124

110

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“…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).…”

mentioning

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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“…The absence of functional Nramp1 in mice leads to unrestrained bacterial replication in the liver and spleen, resulting in a lethal infection. Genetic polymorphisms of the human homologue, NRAMP1, have been linked to susceptibility to various bacterial diseases, including tuberculosis and leprosy, as well as diseases with a suspected bacterial etiological component, including inflammatory bowel disease and rheumatoid arthritis (4).…”

mentioning

confidence: 99%

Host–pathogen interactions: Host resistance factor Nramp1 up-regulates the expression of Salmonella pathogenicity island-2 virulence genes

Zaharik

Vallance

Puente

et al. 2002

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

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Nramp1 (Natural resistance-associated macrophage protein-1; also known as Slc11a1) is a host resistance gene that provides protection against several intracellular pathogens, including Salmonella enterica serovar Typhimurium. Little is known about the dynamic interplay that occurs between mammalian host resistance determinants such as Nramp1 and pathogens during infection. To explore these interactions, we examined the effect of Nramp1 on expression of Salmonella typhimurium (STM) virulence factors. We demonstrate that Salmonella pathogenicity island 2 (SPI2) is essential for replication of STM in spleens of infected Nramp1 ϩ/ϩ mice. Furthermore, the presence of Nramp1 in transfected cell lines and congenic knockout mice resulted in the up-regulation of STM SPI2-associated virulence genes critical for intramacrophage survival. This Nramp1-dependent up-regulation of SPI2 was mimicked in vitro by chelation of iron, demonstrating the iron-responsive nature of expression of STM SPI2-associated virulence genes. We propose that acquisition of SPI2 by S. enterica not only enabled this bacterium to become an effective intracellular pathogen but also allowed the bacterium to withstand the effects of macrophage defense mechanisms such as Nramp1 early in the evolution of its pathogenic character. These dynamic Nramp1-pathogen interactions may be essential for regulating the course of an infection. This study demonstrates the presence of a previously undescribed direct influence of a mammalian innate host resistance locus on a pathogen at the genetic level.

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SLC11A1 (formerly NRAMP1) and disease resistance. Microreview

Cited by 218 publications

References 96 publications

Targeted removal of bioavailable metal as a detoxification strategy for carbon nanotubes

Targeted removal of bioavailable metal as a detoxification strategy for carbon nanotubes

Evolution of Differences in Transport Function in Slc11a Family Members

Host–pathogen interactions: Host resistance factor Nramp1 up-regulates the expression of Salmonella pathogenicity island-2 virulence genes

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