Human dendritic cell-specific ICAM-3-grabbing non-integrin downstream signaling alleviates renal fibrosis via Raf-1 activation in systemic candidiasis
Journal
Cellular & molecular immunology
Journal Volume
16
Journal Issue
3
Pages
288
Date Issued
2019-03
Author(s)
Abstract
We generated a human dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN) transgenic mouse in which renal tubular epithelial cells expressed DC-SIGN. The transgenic mice were infected with Candida albicans intravenously to study how DC-SIGN expression affected the pathogenesis of systemic candidiasis. We discovered that, while C. albicans infection induced renal fibrosis in both transgenic and littermate control mice, the transgenic mice had significantly lower levels of Acta2, Col1a2, Col3a1, and Col4a1 mRNA transcripts compared to the controls. KIM-1, an emerging biomarker for kidney injury, along with Tnf, Il6, and Tgfb1 transcripts, were lower in infected transgenic mice, and yet, the levels of Il10 remained comparable to the controls. While renal CD45+ infiltrating cells were the source of Tnf, Il6, and Il10, LTL+ renal proximal tubular epithelial cells were TGF-β1 producers in both infected transgenic and littermate controls. DC-SIGN-expressing tubular epithelial cells produced less TGF-β1 in response to C. albicans infection. In vivo experiments demonstrated that renal proximal tubular epithelial cell production of TGF-β1 was key to C. albicans-induced renal fibrosis and injury. Infection of transgenic mice induced a marked increase of phosphorylated Raf-1 and p38 in the kidney. However, ERK1/2 and JNK phosphorylation was more pronounced in the infected-littermate controls. Interestingly, treating the infected transgenic mice with a Raf-1 inhibitor increased the levels of the Tgfb1, Kim1, and Acta2 transcripts. These results indicate that DC-SIGN signaling, through activation of Raf-1 and p38 and suppression of JNK and ERK1/2 phosphorylation, reduces TGF-β1 production and C. albicans-induced renal fibrosis. Our study reveals for the first time the effect of DC-SIGN expression on C. albicans-induced renal fibrosis.
Subjects
Candida albicans; DC-SIGN; Raf-1; Renal fibrosis; TGF-β1
SDGs
Other Subjects
biological marker; intercellular adhesion molecule 3; interleukin 10; interleukin 6; messenger RNA; mitogen activated protein kinase 1; mitogen activated protein kinase 3; mitogen activated protein kinase p38; Raf protein; stress activated protein kinase; transforming growth factor beta1; tumor necrosis factor; cell adhesion molecule; cell surface receptor; DC-specific ICAM-3 grabbing nonintegrin; lectin; mitogen activated protein kinase p38; Raf protein; transforming growth factor beta1; Acta2 gene; animal experiment; animal model; animal tissue; Article; candidiasis; Col1a2 gene; Col3a1 gene; Col4a1 gene; controlled study; cytokine production; DC SIGN gene; dendritic cell; enzyme phosphorylation; epithelium cell; gene expression; genetic transcription; human; human cell; in vivo study; invasive candidiasis; kidney fibrosis; kidney tubule cell; nonhuman; pathogenesis; protein phosphorylation; signal transduction; transgene; animal; Candida albicans; cell culture; disease model; fibrosis; genetics; immunology; kidney; metabolism; mouse; pathology; phosphorylation; physiology; signal transduction; transgenic mouse; Animals; Candida albicans; Candidiasis; Cell Adhesion Molecules; Cells, Cultured; Dendritic Cells; Disease Models, Animal; Epithelial Cells; Fibrosis; Humans; Kidney; Lectins, C-Type; Mice; Mice, Transgenic; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-raf; Receptors, Cell Surface; Signal Transduction; Transforming Growth Factor beta1
Publisher
CHIN SOCIETY IMMUNOLOGY
Type
journal article