title: Regulation of macrophage arginase expression and tumor growth by the Ron receptor tyrosine kinase.
abstract: M1 activation of macrophages promotes inflammation and immunity to intracellular pathogens, whereas M2 macrophage activation promotes resolution of inflammation, wound healing, and tumor growth. These divergent phenotypes are characterized, in part, by the expression of inducible NO synthase and arginase I (Arg1) in M1 versus M2 activated macrophages, respectively. In this study, we demonstrate that the Ron receptor tyrosine kinase tips the balance of macrophage activation by attenuating the M1 phenotype while promoting expression of Arg1 through a Stat6-independent mechanism. Induction of the Arg1 promoter by Ron is mediated by an AP-1 site located 433 bp upstream of the transcription start site. Treatment of primary macrophages with macrophage stimulating protein, the ligand for Ron, induces potent MAPK activation, upregulates Fos, and enhances binding of Fos to the AP-1 site in the Arg1 promoter. In vivo, Arg1 expression in tumor-associated macrophages (TAMs) from Ron(-/-) mice was significantly reduced compared with that in TAMs from control animals. Furthermore, we show that Ron is expressed specifically by Tie2-expressing macrophages, a TAM subset that exhibits a markedly skewed M2 and protumoral phenotype. Decreased Arg1 in TAMs from Ron(-/-) mice was associated with reduced syngeneic tumor growth in these animals. These findings indicate that Ron induces Arg1 expression in macrophages through a previously uncharacterized AP-1 site in the Arg1 promoter and that Ron could be therapeutically targeted in the tumor microenvironment to inhibit tumor growth by targeting expression of Arg1.
authors.affiliation: Graduate Program in Pathobiology, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Sharda
authors.forename: Shan
authors.initials: S
authors.lastname: Yu
authors.forename: Manujendra
authors.initials: M
authors.lastname: Ray
authors.forename: Mario Leonardo
authors.initials: ML
authors.lastname: Squadrito
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Morris
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Hankey
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D002469:Cell Separation; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D018808:Transcription Factor AP-1; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; C544448:Arg1 protein, mouse; D001119:Arginase