title: HMGB1 enhances the protumoral activities of M2 macrophages by a RAGE-dependent mechanism.
abstract: The monocyte-macrophage lineage shows a high degree of diversity and plasticity. Once they infiltrate tissues, they may acquire two main functional phenotypes, being known as the classically activated type 1 macrophages (M1) and the alternative activated type 2 macrophages (M2). The M1 phenotype can be induced by bacterial products and interferon-γ and exerts a cytotoxic effect on cancer cells. Conversely, the alternatively activated M2 phenotype is induced by Il-4/IL13 and promotes tumor cell growth and vascularization. Although receptor for advanced glycation end-products (RAGE) engagement in M1 macrophages has been reported by several groups to promote inflammation, nothing is known about the functionality of RAGE in M2 macrophages. In the current study, we demonstrate that RAGE is equally expressed in both macrophage phenotypes and that RAGE activation by high-mobility group protein box1 (HMGB1) promotes protumoral activities of M2 macrophages. MKN45 cells co-cultured with M2 macrophages treated with HMGB1 at different times displayed higher invasive abilities. Additionally, conditioned medium from HMGB1-treated M2 macrophages promotes angiogenesis in vitro. RAGE-targeting knockdown abrogates these activities. Overall, the present findings suggest that HMGB1 may contribute, by a RAGE-dependent mechanism, to the protumoral activities of the M2 phenotype.
authors.affiliation: Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, 3605 San Miguel Ave., Talca, Chile. arojasr@ucm.cl.
authors.forename: Armando
authors.initials: A
authors.lastname: Rojas
authors.affiliation: Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, 3605 San Miguel Ave., Talca, Chile.
authors.forename: Fernando
authors.initials: F
authors.lastname: Delgado-López
authors.affiliation: Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, 3605 San Miguel Ave., Talca, Chile.
authors.forename: Ramón
authors.initials: R
authors.lastname: Perez-Castro
authors.affiliation: Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, 3605 San Miguel Ave., Talca, Chile.
authors.forename: Ileana
authors.initials: I
authors.lastname: Gonzalez
authors.affiliation: Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, 3605 San Miguel Ave., Talca, Chile.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Romero
authors.affiliation: Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, 3605 San Miguel Ave., Talca, Chile.
authors.forename: Israel
authors.initials: I
authors.lastname: Rojas
authors.affiliation: Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, 3605 San Miguel Ave., Talca, Chile.
authors.forename: Paulina
authors.initials: P
authors.lastname: Araya
authors.affiliation: Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, 3605 San Miguel Ave., Talca, Chile.
authors.forename: Carolina
authors.initials: C
authors.lastname: Añazco
authors.affiliation: Pathology Unit, Regional Hospital, Talca, Chile.
authors.forename: Erik
authors.initials: E
authors.lastname: Morales
authors.affiliation: Gastroenterology Unit, Regional Hospital, Talca, Chile.
authors.forename: Jorge
authors.initials: J
authors.lastname: Llanos
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D018920:Coculture Techniques; D015870:Gene Expression / Q000187:drug effects; D024243:HMGB1 Protein / Q000494:pharmacology*; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000145:classification / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C000593871:AGER protein, human; D024243:HMGB1 Protein; D053583:Interleukin-1beta; D000067759:Receptor for Advanced Glycation End Products; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D052247:Nitric Oxide Synthase Type II
keywords: HMGB1; Macrophage polarization; Receptor for advanced glycation end-products (RAGE); Tumor-associated macrophages