Metalloproteinases shed TREM-1 ectodomain from lipopolysaccharide-stimulated human monocytes.
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.
Gómez-Piña
Vanesa
V
Research Unit, La Paz Hospital, Madrid, Spain.
Soares-Schanoski
Alessandra
A
Rodríguez-Rojas
Alexandro
A
Del Fresno
Carlos
C
García
Felipe
F
Vallejo-Cremades
María Teresa
MT
Fernández-Ruiz
Irene
I
Arnalich
Francisco
F
Fuentes-Prior
Pablo
P
López-Collazo
Eduardo
E
D017398:Alternative Splicing / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D006801:Humans; D006868:Hydrolysis; D008070:Lipopolysaccharides / Q000276:immunology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D045726:Metalloproteases / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D012333:RNA, Messenger / Q000302:isolation & purification; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012475:Salmonella / Q000276:immunology; D012995:Solubility