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Caspase-Independent Cell Death by CD300LF (MAIR-V), an Inhibitory Immunoglobulin-Like Receptor on Myeloid Cells¹

Department of Immunology, Institute of Basic Medical Sciences and Center for Tsukuba Advanced Research Alliance, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan

The myeloid-associated Ig-like receptor family (CD300) consists of nine activating or inhibitory cell surface receptors preferentially expressed on myeloid cells and are encoded by the genes in a small cluster on mouse chromosome 11. One of the receptors, CD300LF (MAIR-V), has a long cytoplasmic tail containing two consensus ITIMs and an immunoreceptor tyrosine-based switching motif, suggesting that CD300LF regulates the activation of myeloid cells. However, the functional characteristics of this receptor are still incompletely understood. In this study, we demonstrate that cross-linking CD300LF with anti-CD300LF mAb induced cell death in peritoneal macrophages as well as in several transfectants expressing CD300LF. CD300LF-mediated cell death was dependent on the cytoplasmic region but did not require an ITIM or immunoreceptor tyrosine-based switching motif. Scanning electron microscopy revealed a loss of blebs from the surface of the dead cells mediated by CD300LF, a morphological feature similar to that observed in apoptotic cells. However, CD300LF-mediated cell death was not inhibited by a caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, or autophagy inhibitors, 3-methyladenine or N-acetyl-L-cystein. Moreover, the splicing isoform of a transcription factor, X-box binding protein-1, which is produced in dead cells as a response to endoplasmic reticulum stress, was not detected. Together, these results indicate that CD300LF mediates caspase and endoplasmic reticulum stress-independent cell death by a novel mechanism.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported in part by grants provided by the Ministry of Education, Science, and Culture of Japan.

² Address correspondence and reprint requests to Dr. Akira Shibuya, Department of Immunology, Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-3585, Japan. E-mail address: ashibuya{at}md.tsukuba.ac.jp

³ Abbreviations used in this paper: MAIR, myeloid-associated Ig-like receptor; CLM, CMRF-35-like molecule-1; LMIR, leukocyte mono-Ig-like receptor; DC, dendritic cell; DIgR, DC-derived Ig receptor; 3-MA, 3-methyladenine; NAC, N-Acetyl-L-cystein; MDC, monodansylcadaverine; z-VAD-fmk, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone; PI, propidium iodide; ITSM, immunoreceptor tyrosine-based switching motif; WT, wild type; ER, endoplasmic reticulum; XBP-1, X-box binding protein-1; EM, electron microscope; Siglec, sialic acid-binding Ig-like lectin.