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The solute carrier family 15A4 regulates TLR9 and NOD1 functions in the innate immune system and promotes colitis in mice
- Source :
- Gastroenterology. 140(5)
- Publication Year :
- 2010
-
Abstract
- Background & Aims Solute carrier family 15 (SLC15) A4 is a proton-coupled histidine and oligopeptide cotransporter expressed by the immune and nervous systems and associated with disorders such as inflammatory bowel diseases and systemic lupus erythematosus. High levels of SLC15A4 transcripts were observed in human antigen-presenting cells, including dendritic cells, activated macrophages, and B cells. However, the roles of SLC15A4 in the immune regulation are not known. We investigated the function of SLC15A4 in the innate immune system. Methods We created SLC15A4-deficient ( SLC15A4 −/− ) mice and compared Toll-like receptor 9 and NOD1-dependent innate immune responses between SLC15A4 −/− and control ( SLC15A4 +/+ ) mice. Results SLC15A4 deficiency impaired CpG-induced production of interleukin-12, interleukin-15, and interleukin-18 by dendritic cells. Correspondingly, SLC15A4 −/− mice developed a less severe form of Th1-dependent colitis than SLC15A4 +/+ mice. Increased lysosomal histidine, in the absence of SLC15A4, appears to negatively regulate Toll-like receptor 9 function by inhibiting the proteolytic activities of cathepsins B and L. SLC15A4 −/− mice also had a severe defect in NOD1-dependent cytokine production, indicating that SLC15A4 functions as a transporter of the NOD1 ligand. Conclusions SLC15A4 promotes colitis through Toll-like receptor 9 and NOD1-dependent innate immune responses. Histidine homeostasis within intracellular compartments is important for eliciting effective innate immune responses.
- Subjects :
- Male
Biology
Mice
Immune system
Nod1 Signaling Adaptor Protein
NOD1
Animals
Cells, Cultured
Toll-like receptor
Innate immune system
Hepatology
Innate lymphoid cell
Gastroenterology
CCL18
Membrane Transport Proteins
Dendritic cell
DNA
Colitis
Immunohistochemistry
Immunity, Innate
Cell biology
Mice, Inbred C57BL
Disease Models, Animal
Gene Expression Regulation
Toll-Like Receptor 9
Immunology
Histidine homeostasis
Female
Subjects
Details
- ISSN :
- 15280012
- Volume :
- 140
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Gastroenterology
- Accession number :
- edsair.doi.dedup.....6bd0d83ad6a6eac36015aef20a8d4288