title: LDL receptor-related protein-1 regulates NFκB and microRNA-155 in macrophages to control the inflammatory response.
abstract: LDL receptor-related protein-1 (LRP1) is an endocytic and cell-signaling receptor. In mice in which LRP1 is deleted in myeloid cells, the response to lipopolysaccharide (LPS) was greatly exacerbated. LRP1 deletion in macrophages in vitro, under the control of tamoxifen-activated Cre-ER(T) fusion protein, robustly increased expression of proinflammatory cytokines and chemokines. In LRP1-expressing macrophages, proinflammatory mediator expression was regulated by LRP1 ligands in a ligand-specific manner. The LRP1 agonists, α2-macroglobulin and tissue-type plasminogen activator, attenuated expression of inflammatory mediators, even in the presence of LPS. The antagonists, receptor-associated protein (RAP) and lactoferrin (LF), and LRP1-specific antibody had the entirely opposite effect, promoting inflammatory mediator expression and mimicking LRP1 deletion. NFκB was rapidly activated in response to RAP and LF and responsible for the initial increase in expression of proinflammatory mediators. RAP and LF also significantly increased expression of microRNA-155 (miR-155) after a lag phase of about 4 h. miR-155 expression reflected, at least in part, activation of secondary cell-signaling pathways downstream of TNFα. Although miR-155 was not involved in the initial induction of cytokine expression in response to LRP1 antagonists, miR-155 was essential for sustaining the proinflammatory response. We conclude that LRP1, NFκB, and miR-155 function as members of a previously unidentified system that has the potential to inhibit or sustain inflammation, depending on the continuum of LRP1 ligands present in the macrophage microenvironment.
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA 92093; Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mantuano
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA 92093;
authors.forename: Coralie
authors.initials: C
authors.lastname: Brifault
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA 92093;
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lam
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA 92093; Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.
authors.forename: Pardis
authors.initials: P
authors.lastname: Azmoon
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA 92093;
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Gilder
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA 92093; sgonias@ucsd.edu.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gonias
mesh_terms: D000818:Animals; D007249:Inflammation / Q000517:prevention & control*; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*
chemical_list: D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D016328:NF-kappa B
keywords: LDL receptor-related protein-1; NFκB; lipopolysaccharide; microRNA-155; tissue-type plasminogen activator