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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

Cellular & Molecular Immunology volume 16, pages 288–301 (2019)Cite this article

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.

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Acknowledgements

We are grateful for the gift of the pcDNA3.1 plasmid containing hDC-SIGN cDNA from Dan R. Littman (New York University, School of Medicine, New York, NY, USA). We thank Dr. Ting-Fen Tsai (National Yang-Ming University, Taipei, Taiwan) for the mammalian expression vector pK14TyrPolII-IN2B. The services provided by the Imaging Core, the Flow Cytometric Analyzing and Sorting Core at the Second Core, and the Third Core Laboratories of the Department of Medical Research, National Taiwan University Hospital are gratefully acknowledged. The authors also thank the Laboratory Animal Center of National Taiwan University College of Medicine for providing histopathological analysis. The work was supported by research grants 103-2321-B-002-016 and 104-2321-B-002-049 from the Ministry of Science and Technology (MOST, https://www.most.gov.tw/) and Thematic Research Program AS-105-TP-B08-3 from Academia Sinica (https://www.sinica.edu.tw/index.shtml) to B.A.W.-H.

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Authors and Affiliations

  1. Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China

    Wen-Yu Chen, Sheng-Yang Wu, Ta-Chun Lin & Betty A. Wu-Hsieh

  2. Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan, China

    Shuei-Liong Lin

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  1. Wen-Yu Chen
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Contributions

W.-Y.C. contributed to the conception and design of the work; was devoted to the acquisition, analysis, and interpretation of data; and drafted and finalized the submitted manuscript. S.-Y.W. and T.-C.L. contributed to the design of the work and created materials that were required for the work. S.-L.L. contributed to the conception of the work and provided reagents required for the work. B.A.W.-H. contributed to the conception and design of the work, was devoted to the interpretation of data, drafted and finalized the manuscript, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Betty A. Wu-Hsieh.

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Chen, WY., Wu, SY., Lin, TC. et al. Human dendritic cell-specific ICAM-3-grabbing non-integrin downstream signaling alleviates renal fibrosis via Raf-1 activation in systemic candidiasis. Cell Mol Immunol 16, 288–301 (2019). https://doi.org/10.1038/s41423-018-0161-5

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