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* Research Unit, "La Paz" Hospital, Madrid, Spain;
Discovery Unit, EMPIREO, Madrid, Spain;
Emergency Service and Department of Medicine, "La Paz" Hospital Medical School, Universidad Autónoma de Madrid, Madrid, Spain; and
Cardiovascular Research Center, Spanish National Research Council and the Catalan Institute of Cardiovascular Sciences, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Triggering receptors expressed on myeloid cell (TREM) proteins are a family of cell surface receptors that participate in diverse cellular processes such as inflammation, coagulation, and bone homeostasis. TREM-1, in particular, is expressed on neutrophils and monocytes and is a potent amplifier of inflammatory responses. LPS and other microbial products induce up-regulation of cell surface-localized TREM-1 and the release of its soluble form, sTREM-1. Two hypotheses have been advanced to explain the origin of sTREM-1: alternative splicing of TREM-1 mRNA and proteolytic cleavage(s) of mature, membrane-anchored TREM-1. In this report, we present conclusive evidence in favor of the proteolytic mechanism of sTREM-1 generation. No alternative splicing forms of TREM-1 were detected in monocytes/macrophages. Besides, metalloproteinase inhibitors increased the stability of TREM-1 at the cell surface while significantly reducing sTREM-1 release in cultures of LPS-challenged human monocytes and neutrophils. We conclude that metalloproteinases are responsible for shedding of the TREM-1 ectodomain through proteolytic cleavage of its long juxtamembrane linker.
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1 This work was supported by grants from the "Ministerio de Educación y Ciencia" (SAF 1256) and from "Fundación Médica de la Mutua Madrileña de Automovilística" (to E.L.-C.).
2 Address correspondence and reprint requests to Dr. Eduardo López-Collazo, Research Unit, "La Paz" Hospital, Madrid 28046, Spain. E-mail address: elopezc.hulp{at}salud.madrid.org
3 Abbreviations used in this paper: TREM, triggering receptors expressed on myeloid cells; sTREM, soluble form of TREM; MMP, matrix metalloproteinase; PI, propidium iodide; INH, standard proteinase inhibitor mixture.
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