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Human dendritic cell-specific ICAM-3-grabbing non-integrin downstream signaling alleviates renal fibrosis via Raf-1 activation in systemic candidiasis.

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.

journal_name

Cell Mol Immunol

journal_title

Cellular & molecular immunology

authors

Chen WY,Wu SY,Lin TC,Lin SL,Wu-Hsieh BA

doi

10.1038/s41423-018-0161-5

subject

Has Abstract

pub_date

2019-03-01 00:00:00

pages

288-301

issue

eissn

1672-7681

issn

2042-0226

pii

10.1038/s41423-018-0161-5

journal_volume

pub_type

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Human dendritic cell-specific ICAM-3-grabbing non-integrin downstream signaling alleviates renal fibrosis via Raf-1 activation in systemic candidiasis.