Lymph node fibroblastic reticular cells deposit fibrosis-associated collagen following organ transplantation
Xiaofei Li, … , Jonathan S. Bromberg, Reza Abdi
Xiaofei Li, … , Jonathan S. Bromberg, Reza Abdi
Published June 29, 2020
Citation Information: J Clin Invest. 2020;130(8):4182-4194. https://doi.org/10.1172/JCI136618.
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Lymph node fibroblastic reticular cells deposit fibrosis-associated collagen following organ transplantation

Abstract

Although the immune response within draining lymph nodes (DLNs) has been studied for decades, how their stromal compartment contributes to this process remains to be fully explored. Here, we show that donor mast cells were prominent activators of collagen I deposition by fibroblastic reticular cells (FRCs) in DLNs shortly following transplantation. Serial analysis of the DLN indicated that the LN stroma did not return to its baseline microarchitecture following organ rejection and that the DLN contained significant fibrosis following repetitive organ transplants. Using several FRC conditional-knockout mice, we show that induction of senescence in the FRCs of the DLN resulted in massive production of collagen I and a proinflammatory milieu within the DLN. Stimulation of herpes virus entry mediator (HVEM) on FRCs by its ligand LIGHT contributed chiefly to the induction of senescence in FRCs and overproduction of collagen I. Systemic administration of ex vivo–expanded FRCs to mice decreased DLN fibrosis and strengthened the effect of anti-CD40L in prolonging heart allograft survival. These data demonstrate that the transformation of FRCs into proinflammatory myofibroblasts is critically important for the maintenance of a proinflammatory milieu within a fibrotic DLN.

Authors

Xiaofei Li, Jing Zhao, Vivek Kasinath, Mayuko Uehara, Liwei Jiang, Naima Banouni, Martina M. McGrath, Takaharu Ichimura, Paolo Fiorina, Dario R. Lemos, Su Ryon Shin, Carl F. Ware, Jonathan S. Bromberg, Reza Abdi

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Figure 2

Repetitive skin transplantation induces fibrosis in DLNs.

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Repetitive skin transplantation induces fibrosis in DLNs. (A) Collagen I...
(A) Collagen I fibers (red) in the DLNs (axillary LNs, DLNRep) of mice following repetitive skin transplantation in comparison with the axillary LNs of age-matched naive mice and semiquantitative analysis. Scale bar: 1500 μm. n = 5. (B) Costaining of Meca-79+ HEVs (green) and Lyve-1+ lymphatic vessels (green) with collagen I fibers (red) and fibronectin fibers (red) in DLNRep and age-matched naive LNs. Scale bars: 100 μm. (C) Masson’s trichrome stain of fibrosis in DLNRep and age-matched naive LNs. Scale bars: 50 μm. (D) Fluorescence micrographs showing expression of the myofibroblast marker α-SMA by PDPN+ FRCs in DLNRep and naive LNs. Scale bars: 100 μm. (E) Gene expression levels of fibrosis markers and TGF-β signaling molecules in the DLNRep and LNs of naive mice. n = 4. The percentage of the areas stained positive in the fluorescence micrographs was assessed in 3–6 random microscopic fields for each mouse. Data are presented as the mean ± SD. *P < 0.05 and **P < 0.01, by Student’s t test.