title: Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney.
abstract: Acute kidney injury (AKI) is a common clinical condition defined as a rapid decline in kidney function. AKI is a global health burden, estimated to cause 2 million deaths annually worldwide. Unlike AKI in the young, which is reversible, AKI in the elderly often leads to end-stage renal disease, and the mechanism that prevents kidney repair in the elderly is unclear. Here we demonstrate that aged but not young mice developed multiple tertiary lymphoid tissues (TLTs) in the kidney after AKI. TLT size was associated with impaired renal function and increased expression of proinflammatory cytokines and homeostatic chemokines, indicating a possible contribution of TLTs to sustained inflammation after injury. Notably, resident fibroblasts from a single lineage diversified into p75 neurotrophin receptor+(p75NTR+) fibroblasts and homeostatic chemokine-producing fibroblasts inside TLTs, and retinoic acid-producing fibroblasts around TLTs. Deletion of CD4+cells as well as late administration of dexamethasone abolished TLTs and improved renal outcomes. Importantly, aged but not young human kidneys also formed TLTs that had cellular and molecular components similar to those of mouse TLTs. Therefore, the inhibition of TLT formation may offer a novel therapeutic strategy for AKI in the elderly.
authors.affiliation: Department of Nephrology.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Nephrology.
authors.forename: Akiko
authors.initials: A
authors.lastname: Mii
authors.affiliation: Department of Immunology and Cell Biology.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hamazaki
authors.affiliation: Department of Immunology and Cell Biology.
authors.forename: Harumi
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Department of Nephrology.
authors.forename: Hirosuke
authors.initials: H
authors.lastname: Nakata
authors.affiliation: Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Department of Nephrology.
authors.forename: Shingo
authors.initials: S
authors.lastname: Nishiyama
authors.affiliation: Department of Diagnostic Pathology.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Shibuya
authors.affiliation: Department of Diagnostic Pathology.
authors.forename: Hironori
authors.initials: H
authors.lastname: Haga
authors.affiliation: Department of Urology.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ogawa
authors.affiliation: Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.affiliation: Medical Innovation Center, Graduate School of Medicine.
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.affiliation: Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
authors.affiliation: Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.affiliation: Department of Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.affiliation: Institute for Academic Initiatives, Osaka University, Osaka, Japan.|MediCity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyasaka
authors.affiliation: Center for Renal Translational Medicine and Institute of Metabolomic Medicine, Department of Medicine, University of California San Diego, Veteran's Administration San Diego Health Care System, La Jolla, California, USA.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Department of Immunology and Cell Biology.
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Minato
authors.affiliation: Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
authors.affiliation: Department of Nephrology.
authors.forename: Motoko
authors.initials: M
authors.lastname: Yanagita
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology*; D000328:Adult; D000367:Age Factors; D000368:Aged; D000818:Animals; D018925:Chemokines / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology*; D006801:Humans; D007668:Kidney / Q000473:pathology*; D007684:Kidney Tubules; D008221:Lymphoid Tissue / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D012307:Risk Factors
chemical_list: D018925:Chemokines; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse
keywords: kidney; tertiary; lymphoid; tissue; aging