title: The ligand-bound thyroid hormone receptor in macrophages ameliorates kidney injury via inhibition of nuclear factor-κB activities.
abstract: In chronic kidney disease (CKD) patients, inflammation plays a pivotal role in the progression of renal fibrosis. Hypothyroidism is associated with an increased occurrence of atherosclerosis and inflammation, suggesting protective roles of thyroid hormones and their receptors against inflammatory processes. The contribution of thyroid hormone receptors to macrophage differentiation has not been well documented. Here, we focused on the endogenous thyroid hormone receptor α (TRα) in macrophages and examined the role of ligand-bound TRα in macrophage polarization-mediated anti-inflammatory effects. TRα-deficient irradiated chimeric mice showed exacerbated tubulointerstitial injury in a unilateral ureteral obstruction model. Compared with wild-type macrophages, macrophages isolated from the obstructed kidneys of mice lacking TRα displayed increased expression of proinflammatory cytokines that was accompanied by enhanced nuclear translocation of p65. Comparison of TRα-deficient bone marrow-derived macrophages with wild-type macrophages confirmed the propensity of the former cells to produce excessive IL-1β levels. Co-culture of these macrophages with renal epithelial cells induced more severe damage to the epithelial cells via the IL-1 receptor. Our findings indicate that ligand-bound TRα on macrophages plays a protective role in kidney inflammation through the inhibition of NF-κB pathways, possibly by affecting the pro- and anti-inflammatory balance that controls the development of CKD.
authors.affiliation: Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 4093898, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Furuya
authors.affiliation: Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 4093898, Japan.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Laboratory and Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 4093898, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Tamura
authors.affiliation: Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 4093898, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 4093898, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 4093898, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ichijo
authors.affiliation: Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 4093898, Japan.
authors.forename: Soichi
authors.initials: S
authors.lastname: Takizawa
authors.affiliation: Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 4093898, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kaneshige
authors.affiliation: Department of Laboratory and Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 4093898, Japan.
authors.forename: Katsue
authors.initials: K
authors.lastname: Suzuki-Inoue
authors.affiliation: Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 4093898, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000150:complications / Q000473:pathology
chemical_list: C583355:IL1R1 protein, mouse; D053583:Interleukin-1beta; D008024:Ligands; D016328:NF-kappa B; D034741:RNA, Small Interfering; D053573:Receptors, Interleukin-1 Type I; D037021:Thyroid Hormone Receptors alpha; D014284:Triiodothyronine; D052247:Nitric Oxide Synthase Type II