title: Aromatase controls Sjögren syndrome-like lesions through monocyte chemotactic protein-1 in target organ and adipose tissue-associated macrophages.
abstract: Several autoimmune diseases are known to develop in postmenopausal women. However, the mechanism by which estrogen deficiency influences autoimmunity is unknown. Aromatase is an enzyme that converts androgens to estrogens. Herein, we used female aromatase gene knockout (ArKO) mice as a model of estrogen deficiency to investigate the molecular mechanism that underlies the onset and development of autoimmunity. Histological analyses showed that inflammatory lesions in the lacrimal and salivary glands of ArKO mice increased with age. Adoptive transfer of spleen cells or bone marrow cells from ArKO mice into recombination activating gene 2 knockout mice failed to induce the autoimmune lesions. Expression of mRNA encoding proinflammatory cytokines and monocyte chemotactic protein-1 increased in white adipose tissue of ArKO mice and was significantly higher than that in wild-type mice. Moreover, an increased number of inflammatory M1 macrophages was observed in white adipose tissue of ArKO mice. A significantly increased monocyte chemotactic protein-1 mRNA expression of the salivary gland tissue in ArKO was found together with adiposity. Furthermore, the autoimmune lesions in a murine model of Sjögren syndrome were exacerbated by administration of an aromatase inhibitor. These results suggest that aromatase may play a key role in the pathogenesis of Sjögren syndrome-like lesions by controlling the target organ and adipose tissue-associated macrophage.
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan; Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Iwasa
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Arakaki
authors.affiliation: Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Honma
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Ushio
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Kurosawa
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Kujiraoka
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Tsunematsu
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yasusei
authors.initials: Y
authors.lastname: Kudo
authors.affiliation: Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
authors.affiliation: Department of Biochemistry, School of Medicine, Fujita Health University, Toyoake, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Yoshimura
authors.affiliation: Department of Biochemistry, School of Medicine, Fujita Health University, Toyoake, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Harada
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan. Electronic address: ishimaru.n@tokushima-u.ac.jp.
authors.forename: Naozumi
authors.initials: N
authors.lastname: Ishimaru
mesh_terms: D052436:Adipose Tissue, White / Q000166:cytology*; D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000737:chemistry; D015551:Autoimmunity; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D012469:Salivary Glands / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000201:enzymology* / Q000235:genetics
chemical_list: D047072:Aromatase Inhibitors; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; D001141:Aromatase