TY - JOUR
T1 - Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney
AU - Sato, Yuki
AU - Mii, Akiko
AU - Hamazaki, Yoko
AU - Fujita, Harumi
AU - Nakata, Hirosuke
AU - Masuda, Kyoko
AU - Nishiyama, Shingo
AU - Shibuya, Shinsuke
AU - Haga, Hironori
AU - Ogawa, Osamu
AU - Shimizu, Akira
AU - Narumiya, Shuh
AU - Kaisho, Tsuneyasu
AU - Arita, Makoto
AU - Yanagisawa, Masashi
AU - Miyasaka, Masayuki
AU - Sharma, Kumar
AU - Minato, Nagahiro
AU - Kawamoto, Hiroshi
AU - Yanagita, Motoko
N1 - Funding Information:
We are grateful to Tasuku Honjo, Shigekazu Nagata, Toru Nakano, and Takashi Nagasawa for their valuable comments and discussions. We are also greatly appreciative of Ken-ichi Yamamura for providing the P0-Cre mice, and of Frank Costantini for providing the R26ECFP mice. We also thank Tatsuji Haga, Yumiko Tomita, Chiyomi Inoue, Ayaka Morita, and Maki Ozone for their excellent technical assistance. This study was supported by Grant-in-Aid for Scientific Research B (26293202) from the Japan Society for the Promotion of Science (JSPS), CREST from the Japan Science and Technology Agency, and partly by the grants from the TMK Project, Mitsubishi Tanabe Pharma Corporation, Uehara Memorial Foundation, Takeda Science Foundation, and the Sumitomo Foundation.
Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.87680
DO - 10.1172/jci.insight.87680
M3 - Article
C2 - 27699223
AN - SCOPUS:85055611788
SN - 2379-3708
VL - 1
JO - JCI Insight
JF - JCI Insight
IS - 11
M1 - e87680
ER -