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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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 2

Primary cultured kidney epithelial cells express Kim-1 and phagocytose apoptotic cells by a Kim-1–dependent mechanism.

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Primary cultured kidney epithelial cells express Kim-1 and phagocytose a...
(A) Following coculture with apoptotic thymocytes, Kim-1–positive (Kim-1+) (red with blue nuclei [N]) but not Kim-1–negative (Kim-1–) (blue nuclei only [n]) epithelial cells show avid binding (arrowheads) and internalization of fluorescently labeled apoptotic thymocytes (green and blue) (arrows). Note marked ring enhancement of phagosomes with Kim-1, and Kim-1 at the phagocytic cup of bound apoptotic cells. (B) Image of primary cultured rat epithelial cells all expressing cytokeratin (green) but showing heterogenous expression of Kim-1 (red). Scale bars: 10 μm. (C) The number of apoptotic cells bound or phagocytosed per 100 Kim-1–positive or 100 Kim-1–negative epithelial cells following coculture with labeled apoptotic cells and washing to remove bound cells. Note Kim-1–positive cells show avid phagocytosis. **P < 0.001. (D) Phagocytic index (number apoptotic cells/100 phagocytes) of Kim-1–positive primary epithelial cell cultures pretreated with monoclonal anti-rat Kim-1 affinity purified antibodies (15 μg/ml) followed by coculture with labeled apoptotic cells. Epithelial cells were lifted from plates and single epithelial cells in suspension scored for phagocytic index. Note that anti–Kim-1 antibodies directed at the extracellular domain block phagocytosis when compared with cells preincubated with isotype control antibodies. *P < 0.01.