title: The Ron Receptor Tyrosine Kinase Regulates Macrophage Heterogeneity and Plays a Protective Role in Diet-Induced Obesity, Atherosclerosis, and Hepatosteatosis.
abstract: Obesity is a chronic inflammatory disease mediated in large part by the activation of inflammatory macrophages. This chronic inflammation underlies a whole host of diseases including atherosclerosis, hepatic steatosis, insulin resistance, type 2 diabetes, and cancer, among others. Macrophages are generally classified as either inflammatory or alternatively activated. Some tissue-resident macrophages are derived from yolk sac erythromyeloid progenitors and fetal liver progenitors that seed tissues during embryogenesis and have the ability to repopulate through local proliferation. These macrophages tend to be anti-inflammatory in nature and are generally involved in tissue remodeling, repair, and homeostasis. Alternatively, during chronic inflammation induced by obesity, bone marrow monocyte-derived macrophages are recruited to inflamed tissues, where they produce proinflammatory cytokines and exacerbate inflammation. The extent to which these two populations of macrophages are plastic in their phenotype remains controversial. We have demonstrated previously that the Ron receptor tyrosine kinase is expressed on tissue-resident macrophages, where it limits inflammatory macrophage activation and promotes a repair phenotype. In this study, we demonstrate that Ron is expressed in a subpopulation of macrophages during chronic inflammation induced by obesity that exhibit a repair phenotype as determined by the expression of arginase 1. In addition, we demonstrate that the Ron receptor plays a protective role in the progression of diet-induced obesity, hepatosteatosis, and atherosclerosis. These results suggest that altering macrophage heterogeneity in vivo could have the potential to alleviate obesity-associated diseases.
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802; Graduate Program in Physiology, Pennsylvania State University, University Park, PA 16802;
authors.forename: Shan
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802; Graduate Program in Immunology and Infectious Disease, Pennsylvania State University, University Park, PA 16802; and.
authors.forename: Joselyn N
authors.initials: JN
authors.lastname: Allen
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802; Graduate Program in Physiology, Pennsylvania State University, University Park, PA 16802;
authors.forename: Adwitia
authors.identifier: 0000-0003-1974-0116
authors.initials: A
authors.lastname: Dey
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802;
authors.forename: Limin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802; Graduate Program in Molecular Medicine, Pennsylvania State University, University Park, PA 16802.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Balandaram
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802;
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Kennett
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802; Graduate Program in Immunology and Infectious Disease, Pennsylvania State University, University Park, PA 16802; and.
authors.forename: Mingcan
authors.identifier: 0000-0002-7354-7539
authors.initials: M
authors.lastname: Xia
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802; Graduate Program in Immunology and Infectious Disease, Pennsylvania State University, University Park, PA 16802; and.
authors.forename: Na
authors.identifier: 0000-0003-4405-6818
authors.initials: N
authors.lastname: Xiong
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802; Graduate Program in Molecular Medicine, Pennsylvania State University, University Park, PA 16802.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802;
authors.forename: Andrew
authors.initials: A
authors.lastname: Patterson
authors.affiliation: Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802; Graduate Program in Physiology, Pennsylvania State University, University Park, PA 16802; Graduate Program in Immunology and Infectious Disease, Pennsylvania State University, University Park, PA 16802; and Graduate Program in Molecular Medicine, Pennsylvania State University, University Park, PA 16802 phc7@psu.edu.
authors.forename: Pamela A
authors.identifier: 0000-0002-4290-8709
authors.initials: PA
authors.lastname: Hankey-Giblin
mesh_terms: D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology*; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000276:immunology*; D006801:Humans; D007333:Insulin Resistance; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases