Slc11a1, Formerly Nramp1, Is Expressed in Dendritic Cells and Influences Major Histocompatibility Complex Class II Expression and Antigen-Presenting Cell Function

Abstract

Solute carrier family 11 member a1 (Slc11a1; formerly Nramp1) encodes a late endosomal/lysosomal protein/ divalent cation transporter that regulates iron homeostasis in macrophages. During macrophage activation, Slc11a1 has multiple pleiotropic effects on gene regulation and function, including gamma interferon-induced class II expression and antigen-presenting cell function. The wild-type allele at Slc11a1 has been associated with a bias in Th1 cell function in vivo, which is beneficial in resistance to infection against intracellular macrophage pathogens but detrimental in contributing to development of type 1 diabetes. The extent to which this depends on macrophage versus dendritic cell (DC) function is not known. Here we show that Slc11a1 is expressed in late endosomes and/or lysosomes of CD11c ؉ DCs. DCs from mutant and congenic wild-type mice upregulate interleukin-12 (IL-12) and IL-10 mRNA in response to lipopolysaccharide (LPS) stimulation, but the ratio of IL-10 to IL-12 is higher in unstimulated DCs and DCs stimulated for 15 h with LPS from mutant mice than from wild-type mice. DCs from wild-type mice upregulate major histocompatibility complex class II in response to LPS more efficiently than DCs from mutant mice. Unstimulated DCs from wild-type and mutant mice present ovalbumin (OVA) peptide with an efficiency equivalent to that of an OVA-specific CD4 T-cell line, but DCs from wild-type mice are more efficient at processing and presenting OVA or Leishmania activator of cell kinase (LACK) protein to OVA-and LACK-specific T cells. These data indicate that wild-type Slc11a1 expressed in DCs may play a role both in determining resistance to infectious disease and in susceptibility to autoimmune disease such as type 1 diabetes.

Slc11a1Enhances the Autoimmune Diabetogenic T-Cell Response by Altering Processing and Presentation of Pancreatic Islet Antigens

“…The protein structural characteristics of Slc11a1, i.e., 12-transmembrane domains and a transport motif, indicate a function as an ion channel and a transporter (5,8). Intracellular staining of Slc11a1 in macrophages and dendritic cells demonstrated that the protein is restricted to intravacuolar compartments, especially late endosomes and lysosomes (7,9,10). A glycine to aspartic acid substitution at position 169 (G169D) within the fourth transmembrane domain of Slc11a1 is present in many mouse strains and reduces Slc11a1 expression on the phagosomal membrane (11,12).…”

“…Slc11a1 has been characterized primarily for its ability to mediate resistance to intracellular pathogens such as Salmonella and Leishmania via its expression in macrophages (5,6). Moreover, recently, Slc11a1 was shown to be expressed in dendritic cells (7). The protein structural characteristics of Slc11a1, i.e., 12-transmembrane domains and a transport motif, indicate a function as an ion channel and a transporter (5,8).…”

Evolution of Differences in Transport Function in Slc11a Family Members

“…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).…”

“…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).…”

Estudo do envolvimento dos loci reguladores da reação inflamatória aguda na determinação da sensibilidade ou resistência ao choque endotóxico induzido por lipopolissacarídeo.

“…Além disso, interage na produção de IFN-γ e IL-1 (KITA et al, 1992;RAMARATHINAM et al, 1993), e na expressão de moléculas do complexo principal de histocompatibilidade (LANG et al, 1997;WOJCIECHOWSKI et al, 1999;STOBER et al, 2007).…”