Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury
Conrad A. Farrar, David Tran, Ke Li, Weiju Wu, Qi Peng, Wilhelm Schwaeble, Wuding Zhou, Steven H. Sacks
Conrad A. Farrar, David Tran, Ke Li, Weiju Wu, Qi Peng, Wilhelm Schwaeble, Wuding Zhou, Steven H. Sacks
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Research Article Nephrology

Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury

Abstract

Physiochemical stress induces tissue injury as a result of the detection of abnormal molecular patterns by sensory molecules of the innate immune system. Here, we have described how the recently discovered C-type lectin collectin-11 (CL-11, also known as CL-K1 and encoded by COLEC11) recognizes an abnormal pattern of L-fucose on postischemic renal tubule cells and activates a destructive inflammatory response. We found that intrarenal expression of CL-11 rapidly increases in the postischemic period and colocalizes with complement deposited along the basolateral surface of the proximal renal tubule in association with L-fucose, the potential binding ligand for CL-11. Mice with either generalized or kidney-specific deficiency of CL-11 were strongly protected against loss of renal function and tubule injury due to reduced complement deposition. Ex vivo renal tubule cells showed a marked capacity for CL-11 binding that was induced by cell stress under hypoxic or hypothermic conditions and prevented by specific removal of L-fucose. Further analysis revealed that cell-bound CL-11 required the lectin complement pathway–associated protease MASP-2 to trigger complement deposition. Given these results, we conclude that lectin complement pathway activation triggered by ligand–CL-11 interaction in postischemic tissue is a potent source of acute kidney injury and is amenable to sugar-specific blockade.

Authors

Conrad A. Farrar, David Tran, Ke Li, Weiju Wu, Qi Peng, Wilhelm Schwaeble, Wuding Zhou, Steven H. Sacks

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Figure 7

Sugar specificity of CL-11 binding to stressed renal tubule cells.

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Sugar specificity of CL-11 binding to stressed renal tubule cells. (A) R...
(A) Representative immunofluorescence images of bound rCL-11 in hypothermia-stressed Colec11–/– RTECs following incubation of the cells with rCL-11, which had been pretreated with PBS, L-fucose, or D-galactose, demonstrating that L-fucose–treated rCL-11 had reduced binding to the cells compared with that seen with PBS or D-galactose treatment. Scale bars: 10 μm. (B) Quantification of bound rCL-11 in the RTECs shown in A. Data shown are from 10 individual images and representative of 3 independent experiments. ****P < 0.001, by 1-way ANOVA. (C) Representative fluorescence images of L-fucose (green) in hypothermia-stressed Colec11–/– RTECs following pretreatment of the cells with α-L-fucosidase or β-gal, as detected by the fluorescein-conjugated plant lectin LTL, demonstrating that fucosidase treatment reduced L-fucose residues on the cells. Scale bars: 12.5 μm. (D) Representative immunofluorescence images of bound rCL-11 (red) in the cells shown in C, which had been further incubated with rCL-11, demonstrating that fucosidase treatment reduced rCL-11 binding to the cells. Scale bars: 12.5 μm. (E) Quantification of bound rCL-11 in the RTECs shown in D. Data shown are from 6 to 10 individual images and representative of 2 independent experiments. ****P < 0.001, by unpaired, 2-tailed Student’s t test.