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JCI Insight. 2016 Jul 21;1(11):e87680.

Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney.

Author information

1
Department of Nephrology.
2
Department of Immunology and Cell Biology.
3
Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto, Japan.
4
Department of Diagnostic Pathology.
5
Department of Urology.
6
Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan.
7
Medical Innovation Center, Graduate School of Medicine.
8
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan.
9
Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
10
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.
11
Institute for Academic Initiatives, Osaka University, Osaka, Japan.; MediCity Research Laboratory, University of Turku, Turku, Finland.
12
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.

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.

KEYWORDS:

kidney; tertiary; lymphoid; tissue; aging

PMID:
27699223
PMCID:
PMC5033938
DOI:
10.1172/jci.insight.87680
[Indexed for MEDLINE]
Free PMC Article

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