The peptide symporter SLC15a4 is essential for the development of systemic lupus erythematosus in murine models

Abstract

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease representing a serious unmet medical need. The disease is associated with the loss of self-tolerance and exaggerated B cell activation, resulting in autoantibody production and the formation of immune complexes that accumulate in the kidney, causing glomerulonephritis. TLR7, an important mediator of the innate immune response, drives the expression of type-1 interferon (IFN), which leads to expression of type-1 IFN induced genes and aggravates lupus pathology. Because the lysosomal peptide symporter slc15a4 is critically required for type-1 interferon production by pDC, and for certain B cell functions in response to TLR7 and TLR9 signals, we considered it as a potential target for pharmacological intervention in SLE. We deleted the slc15a4 gene in C57BL/6, NZB, and NZW mice and found that pristane-challenged slc15a4-/- mice in the C57BL/6 background and lupus prone slc15a4-/- NZB/W F1 mice were both completely protected from lupus like disease. In the NZB/W F1 model, protection persisted even when disease development was accelerated with an adenovirus encoding IFNα, emphasizing a broad role of slc15a4 in disease initiation. Our results establish a non-redundant function of slc15a4 in regulating both innate and adaptive components of the immune response in SLE pathobiology and suggest that it may be an attractive drug target.

The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid–sensing TLRs and ligands to endolysosomes

“…Of considerable interest, the disease-inhibiting effect was also observed in the heterozygous feeble state, albeit not as profoundly as in the homozygous state. Recently, others have also reported similar disease-reducing effects in homozygous and heterozygous Slc15a4 -deleted NZB/W F1 lupus-predisposed mice ( 11 ). These results are of considerable significance since they suggest that even partial pharmacologic inhibition of this transporter may be sufficient to reduce disease progression in humans.…”

“…Our study addressed these possibilities through enhanced-resolution confocal microscopy and quantitative colocalization analysis and showed that indeed Slc15a4 mutant pDCs were defective in the trafficking of TLR9 and its CpG-A ligand into the endolysosomes, an absolute requirement for proper engagement of nucleic acid–sensing TLRs. Since the Slc15a4 feeble mutation or deletion have also been shown to impair TLR7 signaling and cytokine production by pDCs ( 9 , 11 ), we believe that defects similar to those described above for TLR9 are likely to be equally applicable to TLR7 responses, with confirmation required in future experiments.…”

“…Our early studies with congenic lupus-predisposed C57BL/6 Fas lpr mice carrying the function-impairing feeble mutation of Slc15a4 ( 5 ) and subsequent studies by others in the Slc15a4 -deleted pristane model ( 10 ) and in the spontaneous NZB/W F1 lupus model ( 11 ) all showed significant disease reduction. These studies complemented earlier indirect evidence from genome-wide association studies that SLC15A4 may be one of the multitudes of loci contributing to systemic lupus erythemasosus (SLE) and other autoimmune syndromes ( 12 – 16 ).…”

The role of M1 to M2 macrophage polarization in the etiology of idiopathic gastroparesis: GWAS perspective

“…Importantly, it is required for TLR7/9-dependent type I interferon production 13 . SLC15A4 has been associated with disorders such as inflammatory bowel diseases and systemic lupus erythematosus 13 , 14 . High levels of SLC15A4 transcripts were observed in human antigen-presenting cells, including dendritic cells, activated macrophages, and B cells 13 .…”

Chemoproteomics-guided development of SLC15A4 inhibitors with anti-inflammatory activity

“…Specifically, immune cells from Slc15a4 loss-of-function mutant (‘ feeble’ ) and Slc15a4 -/- mice are defective in IFNα as well as TNFα, IL-6 and IL-12 production upon TLR 7-9 stimulation, but otherwise display normal development ( 1 ) ( 4, 10 ). Critically, Slc15a4 feeble and Slc15a4 -/- mice show striking reductions in systemic lupus erythematosus (SLE) manifestations ( 9, 10 ). Finally, genome-wide association studies (GWAS) have revealed SLC15A4 to be associated with inflammatory diseases such as SLE in human populations ( 11–15 ).…”