title: Role of MMPs in orchestrating inflammatory response in human monocytes via a TREM-1-PI3K-NF-κB pathway.
abstract: The MMPs constitute a family of endopeptidases that can cleavage extracellular proteins. They are involved in a number of events; some of these include inflammatory processes. One of its targets is the TREM-1, which has emerged as an important modulator of innate immune responses in mammals. This transmembrane glycoprotein possesses an Ig-like ectodomain readily shed by MMPs to generate sTREM-1. Whereas membrane-anchored TREM-1 amplifies inflammatory responses, sTREM-1 exhibits anti-inflammatory properties. Here we show that sustained cell surface expression of TREM-1 in human monocytes, through metalloproteinase inhibition, counteracts the well-characterized down-regulation of several proinflammatory cytokines during the ET time-frame, also known as M2 or alternative activation. In addition to the cytokines profile, other features of the ET phenotype were underdeveloped when TREM-1 was stabilized at the cell surface. These events were mediated by the signal transducers PI3Ks and Syk. We also show that sTREM-1 counteracts the proinflammatory response obtained by membrane TREM-1 stabilization but failed to induce ET on naïve human monocytes. As the sustained TREM-1 expression at the cell surface suffices to block the progress of a refractory state in human monocytes, our data indicate that TREM-1 and MMPs orchestrate an "adaptive" form of innate immunity by modulating the human monocytes response to endotoxin.
authors.affiliation: Laboratory of Tumor Immunology, IdiPAZ, La Paz Hospital, Madrid, Spain
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gómez-Piña
authors.forename: Eriel
authors.initials: E
authors.lastname: Martínez
authors.forename: Irene
authors.initials: I
authors.lastname: Fernández-Ruíz
authors.forename: Carlos
authors.initials: C
authors.lastname: Del Fresno
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soares-Schanoski
authors.forename: Teresa
authors.initials: T
authors.lastname: Jurado
authors.forename: María
authors.initials: M
authors.lastname: Siliceo
authors.forename: Victor
authors.initials: V
authors.lastname: Toledano
authors.forename: Rosa
authors.initials: R
authors.lastname: Fernández-Palomares
authors.forename: Francisco
authors.initials: F
authors.lastname: García-Rio
authors.forename: Francisco
authors.initials: F
authors.lastname: Arnalich
authors.forename: Subhra K
authors.initials: SK
authors.lastname: Biswas
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Collazo
mesh_terms: D017364:Collagenases / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004731:Endotoxins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D055550:Protein Stability; D011971:Receptors, Immunologic / Q000276:immunology*; D015398:Signal Transduction; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D016207:Cytokines; D004731:Endotoxins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D019869:Phosphatidylinositol 3-Kinases; D017364:Collagenases