Slc11a1 (Nramp1) impairs growth of Salmonella enterica serovar typhimurium in macrophages via stimulation of lipocalin-2 expression.
The expression of the cation transporter Nramp1 (Slc11a1) in late phagolysosomes confers resistance to infection with several intracellular pathogens, such as Salmonella enterica, in mice. The antimicrobial actions of Nramp1 are attributable, in part, to modulation of macrophage immune function and cellular iron metabolism--the latter affecting the availability of the essential nutrient iron for intraphagosomal bacteria. Here, we provide novel evidence that Nramp1 functionality increases the expression of the peptide Lcn2, which exerts its antimicrobial activity by scavenging iron-loaded bacterial siderophores and mediating iron efflux from macrophages. With the use of macrophage cell lines expressing functional or nonfunctional Nramp1, we found significantly elevated Lcn2 mRNA and protein levels in Nramp1-expressing cells. These resulted from Nramp1-mediated alterations in the production of ROS, which stimulated NF-κ B activity and subsequently, Lcn2 transcription. We observed that increased Lcn2 levels in primary Nramp1-positive macrophages resulted in a significant suppression of S. enterica serovar typhimurium growth. Stimulation of Lcn2 expression is a novel mechanism by which Nramp1 confers resistance against infection with the intracellular bacterium S. typhimurium.
Department of Internal Medicine I, Clinical Immunology and Infectious Diseases, Innsbruck Medical University, Innsbruck, Austria.
Gernot
G
Fritsche
Manfred
M
Nairz
Stephen J
SJ
Libby
Ferric C
FC
Fang
Günter
G
Weiss
D000209:Acute-Phase Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D003676:Deferoxamine / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology; D007501:Iron / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000276:immunology*; D012486:Salmonella typhimurium / Q000254:growth & development / Q000276:immunology*; D017262:Siderophores / Q000494:pharmacology; D000099173:Natural Resistance-associated Macrophage Protein 1
D000209:Acute-Phase Proteins; D027682:Cation Transport Proteins; D003676:Deferoxamine; D006861:Hydrogen Peroxide; D007501:Iron; D000071068:Lipocalin-2; D054834:Lipocalins; D016328:NF-kappa B; D015513:Oncogene Proteins; D026361:Reactive Nitrogen Species; D017262:Siderophores; D000099173:Natural Resistance-associated Macrophage Protein 1; C071332:Lcn2 protein, mouse