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Metalloproteinases Shed TREM-1 Ectodomain from Lipopolysaccharide-Stimulated Human Monocytes¹

Vanesa Gómez-Piña^*, Alessandra Soares-Schanoski^*, Alexandro Rodríguez-Rojas^*, Carlos del Fresno^*, Felipe García, María Teresa Vallejo-Cremades^*, Irene Fernández-Ruiz^*, Francisco Arnalich, Pablo Fuentes-Prior and Eduardo López-Collazo^2,*

^* 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.

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 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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