TLR9 signaling in fibroblastic reticular cells regulates peritoneal immunity
Li Xu, … , Timothy R. Billiar, Meihong Deng
Li Xu, … , Timothy R. Billiar, Meihong Deng
Published August 5, 2019
Citation Information: J Clin Invest. 2019;129(9):3657-3669. https://doi.org/10.1172/JCI127542.
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Research Article Immunology Inflammation

TLR9 signaling in fibroblastic reticular cells regulates peritoneal immunity

Abstract

Fibroblastic reticular cells (FRCs), a subpopulation of stromal cells in lymphoid organs and fat-associated lymphoid clusters (FALCs) in adipose tissue, play immune-regulatory roles in the host response to infection and may be useful as a form of cell therapy in sepsis. Here, we found an unexpected major role of TLR9 in controlling peritoneal immune cell recruitment and FALC formation at baseline and after sepsis induced by cecal ligation and puncture (CLP). TLR9 regulated peritoneal immunity via suppression of chemokine production by FRCs. Adoptive transfer of TLR9-deficient FRCs more effectively decreased mortality, bacterial load, and systemic inflammation after CLP than WT FRCs. Importantly, we found that activation of TLR9 signaling suppressed chemokine production by human adipose tissue–derived FRCs. Together, our results indicate that TLR9 plays critical roles in regulating peritoneal immunity via suppression of chemokine production by FRCs. These data form a knowledge basis upon which to design new therapeutic strategies to improve the therapeutic efficacy of FRC-based treatments for sepsis and immune dysregulation diseases.

Authors

Li Xu, Yiming Li, Chenxuan Yang, Patricia Loughran, Hong Liao, Rosemary Hoffman, Timothy R. Billiar, Meihong Deng

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Figure 2

B cells are required for the protective effects of Tlr9–/– mice during sepsis.

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B cells are required for the protective effects of Tlr9–/– mice during s...
(A–D) WT and Tlr9–/– mice were subjected to CLP. Plasma and PLF were collected at 18 hours after CLP. (A) Peritoneal B-1 cell numbers. (B) Plasma IgM levels. (C) Peritoneal IgM levels. (D) Peritoneal GM-CSF levels. (E–G) Tlr9–/– mice were treated with CD19 neutralizing antibodies (10 mg/mouse) or control IgG (10 mg/mouse) at 24 hours before CLP. PLF was collected at 18 hours after CLP. (E) Seven-day survival after CLP. Data are from 2 separate experiments. n = 10. *P < 0.05, log-rank test. (F) Bacterial clearance in PLF. Data are from 2 separate experiments. Symbols represent individual mice. *P < 0.05, nonparametric Mann-Whitney U test. (G) Peritoneal IgM levels. For A–D and G, data are shown as mean ± SD from 2 separate experiments. Symbols represent individual mice. *P < 0.05; **P < 0.01; ***P < 0.001, unpaired, 2-tailed Student’s t test.