title: Accumulation of CD11c+CD163+ Adipose Tissue Macrophages through Upregulation of Intracellular 11β-HSD1 in Human Obesity.
abstract: Adipose tissue (AT) macrophages (ATMs) are key players for regulation of AT homeostasis and obesity-related metabolic disorders. However, the phenotypes of human ATMs and regulatory mechanisms of their polarization have not been clearly described. In this study, we investigated human ATMs in both abdominal visceral AT and s.c. AT and proposed an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)-glucocorticoid receptor regulatory axis that might dictate M1/M2 polarization in ATMs. The accumulation of CD11c+CD163+ATMs in both visceral AT and s.c. AT of obese individuals was confirmed at the cellular level and was found to be clearly correlated with body mass index and production of reactive oxygen species. Using our in vitro system where human peripheral blood monocytes (hPBMs) were cocultured with Simpson-Golabi-Behmel syndrome adipocytes, M1/M2 polarization was found to be dependent on 11β-HSD1, an intracellular glucocorticoid reactivating enzyme. Exposure of hPBMs to cortisol-induced expression of CD163 and RU-486, a glucocorticoid receptor antagonist, significantly abrogated CD163 expression through coculture of mature adipocytes with hPBMs. Moreover, 11β-HSD1 was expressed in crown ATMs in obese AT. Importantly, conditioned medium from coculture of adipocytes with hPBMs enhanced proliferation of human breast cancer MCF7 and MDA-MB-231 cells. In summary, the phenotypic switch of ATMs from M2 to mixed M1/M2 phenotype occurred through differentiation of adipocytes in obese individuals, and upregulation of intracellular 11β-HSD1 might play a role in the process.
authors.affiliation: Center for Translational Medicine, Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Department of Hematology-Oncology, National University of Singapore, Singapore 119228.
authors.forename: Vivien
authors.initials: V
authors.lastname: Koh
authors.affiliation: Department of Hematology-Oncology, National University of Singapore, Singapore 119228.
authors.forename: Ley-Fang
authors.initials: LF
authors.lastname: Kua
authors.affiliation: Department of Surgery, National University of Singapore, Singapore 119228.
authors.forename: Jimmy
authors.initials: J
authors.lastname: So
authors.affiliation: Department of Surgery, National University of Singapore, Singapore 119228.
authors.forename: Lomanto
authors.initials: L
authors.lastname: Davide
authors.affiliation: Center for Translational Medicine, Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
authors.forename: Kee Siang
authors.identifier: 0000-0001-9330-5783
authors.initials: KS
authors.lastname: Lim
authors.affiliation: Center for Translational Medicine, Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
authors.forename: Sven Hans
authors.initials: SH
authors.lastname: Petersen
authors.affiliation: Center for Translational Medicine, Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.|Department of Hematology-Oncology, National University of Singapore, Singapore 119228.
authors.forename: Wei-Peng
authors.initials: WP
authors.lastname: Yong
authors.affiliation: Department of Surgery, National University of Singapore, Singapore 119228.
authors.forename: Asim
authors.initials: A
authors.lastname: Shabbir
authors.affiliation: Center for Translational Medicine, Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599; kojikono@fmu.ac.jp.|Department of Surgery, National University of Singapore, Singapore 119228.|Department of Organ Regulatory Surgery, Fukushima Medical University, Fukushima 960-1295, Japan; and.|Department of Advanced Cancer Immunotherapy, Fukushima Medical University, Fukushima 960-1295, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kono
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000473:pathology; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001145:Arrhythmias, Cardiac / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology*; D039521:CD11c Antigen / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000276:immunology*; D005877:Gigantism / Q000276:immunology*; D006330:Heart Defects, Congenital / Q000276:immunology*; D006801:Humans; D008607:Intellectual Disability / Q000276:immunology*; D050152:Intra-Abdominal Fat / Q000276:immunology*; D061986:MCF-7 Cells; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D050507:Subcutaneous Fat, Abdominal / Q000276:immunology*; D015854:Up-Regulation; D055815:Young Adult; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D039521:CD11c Antigen; D000098902:CD163 Antigen; D016207:Cytokines; D011956:Receptors, Cell Surface; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1