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Background

In people with SLE and in the MRL-Faslpr lupus mouse model, macrophages and autoantibodies are central to lupus nephritis. IL-34 mediates macrophage survival and proliferation, is expressed by tubular epithelial cells (TECs), and binds to the cFMS receptor on macrophages and to a newly identified second receptor, PTPRZ.

Methods

To investigate whether IL-34-dependent intrarenal and systemic mechanisms promote lupus nephritis, we compared lupus nephritis and systemic illness in MRL-Faslpr mice expressing IL-34 and IL-34 knockout (KO) MRL-Faslpr mice. We also assessed expression of IL-34 and the cFMS and PTPRZ receptors in patients with lupus nephritis.

Results

Intrarenal IL-34 and its two receptors increase during lupus nephritis in MRL-Faslpr mice. In knockout mice lacking IL-34, nephritis and systemic illness are suppressed. IL-34 fosters intrarenal macrophage accumulation via monocyte proliferation in bone marrow (which increases circulating monocytes that are recruited by chemokines into the kidney) and via intrarenal macrophage proliferation. This accumulation leads to macrophage-mediated TEC apoptosis. We also found suppression of circulating autoantibodies and glomerular antibody deposits in the knockout mice. This is consistent with fewer activated and proliferating intrarenal and splenic B cells in mice lacking IL-34, and with our novel discovery that PTPRZ is expressed by macrophages, B and T cells. These findings appear translatable to human patients with lupus nephritis, whose expression of IL-34, cFMS, and PTPRZ is similar to that seen in the MRL-Faslpr lupus mouse model. Moreover, expression of IL-34 in TECs correlates with disease activity.

Conclusions

IL-34 is a promising novel therapeutic target for patients with lupus nephritis."xsd:string
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http://purl.uniprot.org/citations/30622154http://purl.uniprot.org/core/author"Wada Y."xsd:string
http://purl.uniprot.org/citations/30622154http://purl.uniprot.org/core/author"Iwata Y."xsd:string
http://purl.uniprot.org/citations/30622154http://purl.uniprot.org/core/author"Gonzalez-Sanchez H.M."xsd:string
http://purl.uniprot.org/citations/30622154http://purl.uniprot.org/core/author"Kelley V.R."xsd:string
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http://purl.uniprot.org/citations/30622154http://purl.uniprot.org/core/author"Weinmann-Menke J."xsd:string
http://purl.uniprot.org/citations/30622154http://purl.uniprot.org/core/author"Meineck M."xsd:string
http://purl.uniprot.org/citations/30622154http://purl.uniprot.org/core/date"2019"xsd:gYear
http://purl.uniprot.org/citations/30622154http://purl.uniprot.org/core/name"J Am Soc Nephrol"xsd:string
http://purl.uniprot.org/citations/30622154http://purl.uniprot.org/core/pages"244-259"xsd:string
http://purl.uniprot.org/citations/30622154http://purl.uniprot.org/core/title"IL-34-Dependent Intrarenal and Systemic Mechanisms Promote Lupus Nephritis in MRL-Faslpr Mice."xsd:string
http://purl.uniprot.org/citations/30622154http://purl.uniprot.org/core/volume"30"xsd:string
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