Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney
Yuki Sato ... Hiroshi Kawamoto, Motoko Yanagita
Yuki Sato ... Hiroshi Kawamoto, Motoko Yanagita
Published July 21, 2016
Citation Information: JCI Insight. 2016;1(11):e87680. doi:10.1172/jci.insight.87680.
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Categories: Research Article Nephrology

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

Yuki Sato, Akiko Mii, Yoko Hamazaki, Harumi Fujita, Hirosuke Nakata, Kyoko Masuda, Shingo Nishiyama, Shinsuke Shibuya, Hironori Haga, Osamu Ogawa, Akira Shimizu, Shuh Narumiya, Tsuneyasu Kaisho, Makoto Arita, Masashi Yanagisawa, Masayuki Miyasaka, Kumar Sharma, Nagahiro Minato, Hiroshi Kawamoto, Motoko Yanagita

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Aged mice develop multiple renal tertiary lymphoid tissues (TLTs) after ...

Figure 1

Aged mice develop multiple renal tertiary lymphoid tissues (TLTs) after kidney injury.

(A) Periodic acid-Schiff (PAS) staining and (B) fibrosis scores 45 days after 30-minute ischemic reperfusion injury (IRI) in young and aged mice (n = 4 per group). (C, E, and F) Immunofluorescence analysis of (C) lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), α-smooth muscle actin (αSMA), and CD45; (E) CD3ε and B220; (F) Ki67 and αSMA; and (D) immunohistochemical analysis of peripheral lymph node addressin (PNAd) in inflammatory cell aggregates in aged kidneys at day 45 after 37-minute IRI. (G and H) PAS staining of IRI kidneys of (G) aged mice and (H) young mice at day 45, and (I) the TLT sizes (n = 4 or 5 per group). (J) Ifng and Tnfa mRNA levels of IRI kidneys at day 45 with variable ischemic times in young and aged mice (n = 4 per group). (K) Correlation between TLT sizes and mRNA levels of Ifng and Tnfa in aged IRI kidneys at day 45 with variable ischemic times (n = 16). (L) PAS staining of young and aged kidneys in folic acid (FA) nephropathy (day 21) and unilateral ureteral obstruction (UUO) (day 14) model. (M) Serum creatinine (sCr) concentrations in young and aged mice 21 days after FA treatment (n = 12 or 13 per group) and correlation of sCr with TLT size in aged mice (n = 13). *P < 0.001, **P < 0.01, #P < 0.05 versus control. One-way ANOVA with Tukey’s post-hoc analysis was used to analyze data from (J); a 2-tailed Student’s t test was used for other experiments. Correlation was determined by Pearson’s correlation analysis. Scale bars: (A, C–H, and L) 100 μm. The expression levels were normalized to those of Gapdh and expressed relative to those of young mouse kidney at day 0 (IRI). In (B, I, J, and M), the box corresponds to the first quartile, median (horizontal bar in the box), and third quartile, and the whiskers extend from minimum to maximum values.