Kidney injury molecule–1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells
Takaharu Ichimura, … , Jeremy S. Duffield, Joseph V. Bonventre
Takaharu Ichimura, … , Jeremy S. Duffield, Joseph V. Bonventre
Published April 15, 2008
Citation Information: J Clin Invest. 2008;118(5):1657-1668. https://doi.org/10.1172/JCI34487.
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Research Article Nephrology

Kidney injury molecule–1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells

Abstract

Following injury, the clearance of apoptotic and necrotic cells is necessary for mitigation and resolution of inflammation and tissue repair. In addition to macrophages, which are traditionally assigned to this task, neighboring epithelial cells in the affected tissue are postulated to contribute to this process. Kidney injury molecule–1 (KIM-1 or TIM-1) is an immunoglobulin superfamily cell-surface protein not expressed by cells of the myeloid lineage but highly upregulated on the surface of injured kidney epithelial cells. Here we demonstrate that injured kidney epithelial cells assumed attributes of endogenous phagocytes. Confocal images confirm internalization of apoptotic bodies within KIM-1–expressing epithelial cells after injury in rat kidney tubules in vivo. KIM-1 was directly responsible for phagocytosis in cultured primary rat tubule epithelial cells and also porcine and canine epithelial cell lines. KIM-1 was able to specifically recognize apoptotic cell surface-specific epitopes phosphatidylserine, and oxidized lipoproteins, expressed by apoptotic tubular epithelial cells. Thus, KIM-1 is the first nonmyeloid phosphatidylserine receptor identified to our knowledge that transforms epithelial cells into semiprofessional phagocytes.

Authors

Takaharu Ichimura, Edwin J.P.v. Asseldonk, Benjamin D. Humphreys, Lakshman Gunaratnam, Jeremy S. Duffield, Joseph V. Bonventre

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Figure 3

KIM-1–expressing kidney epithelial cell lines avidly bind and phagocytose apoptotic and necrotic material.

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KIM-1–expressing kidney epithelial cell lines avidly bind and phagocytos...
(A) KIM-1 (red) in a KIM1-PK1 cell (left panel) is expressed at high levels (arrows) at the point of binding of multiple apoptotic thymocytes (green and blue) and is part of the initial phagocytic cup (arrowhead). Scale bar: 5 μm. At later time points (right panel), KIM-1 remains associated with the internalized apoptotic cell, resulting in ring enhancement (arrow) of the apoptotic body. The cell border is highlighted by broken lines. Scale bar: 10 μm. (B) Multiple apoptotic thymocytes labeled with CMFDA (green) were localized intracellularly in KIM-1–expressing cells after coculture. Internalized apoptotic thymocytes are visualized in the confocal plane of cortical actin filaments (red) in this confocal image confirming internalization. Cell nuclei (N) are highlighted. Scale bar: 10 μm. (C) DIC with fluorescence (green) microscopic images of KIM1-PK1 cells confirm ingestion of CMFDA-labeled (green) apoptotic LLC-PK1 cells (left panel) or sonicated LLC-PK1 cell debris (middle panel). pCDNA-PK1 cells in the same experiment showing no phagocytosis of apoptotic cells (right panel). These microscopic studies confirm internalization of fluorescent apoptotic or necrotic cell debris (arrowheads). Original magnification, ×60.