Slc11a1 (Nramp1) impairs growth of Salmonella enterica serovar typhimurium in macrophages via stimulation of lipocalin-2 expression

Journal of Leukocyte Biology

Gernot Fritsche²  Manfred Nairz²  Günter Weiss²  Stephen J. Libby¹  Ferric C. Fang  and¹ 

[1]  Departments of Laboratory Medicine and Microbiology, University of Washington School of Medicine, Seattle, Washington, USA Department of Internal Medicine I, Clinical Immunology and Infectious Diseases, Innsbruck Medical University, Innsbruck, Austria;Department of Internal Medicine I, Clinical Immunology and Infectious Diseases, Innsbruck Medical University, Innsbruck, Austria;

关键词: NF-κB;    reactive nitrogen species;    desferrioxamine;    iron;    siderophores;   

DOI  :  10.1189/jlb.1111554

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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 metabolismthe 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-κB 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.

【 授权许可】

Unknown