Fibrosis-memory is mediated by IL-3–producing T cells and drives progression of fibrosis
Simone Buchtler, Antje Frühauf, Sophia Neumayer, Kathrin Schmidbauer, Yvonne Talke, Frederike Winter-Köhler, Saidou Balam, Karin Landgraf, Claudia Gebhard, Michael Rehli, Florian Volker Schlieckau, Maria Beck, Florian Günther, Martin Fleck, Kerstin Renner, Matthias Mack
Simone Buchtler, Antje Frühauf, Sophia Neumayer, Kathrin Schmidbauer, Yvonne Talke, Frederike Winter-Köhler, Saidou Balam, Karin Landgraf, Claudia Gebhard, Michael Rehli, Florian Volker Schlieckau, Maria Beck, Florian Günther, Martin Fleck, Kerstin Renner, Matthias Mack
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Research Article Immunology Nephrology

Fibrosis-memory is mediated by IL-3–producing T cells and drives progression of fibrosis

Abstract

Repetitive injuries are an important trigger of progressive fibrosis. To study if repetitive injuries induce an accelerated profibrotic process, also called “fibrosis-memory,” we established an experimental system with two consecutive, clearly separated insults in a model of renal fibrosis with reversible and irreversible unilateral ureteral obstruction. We found that a preceding fibrotic event of one kidney markedly enhanced subsequent development of fibrosis in the contralateral kidney. Aggravation of fibrosis during the second insult was dependent on memory CD4+ T cells. T cell depletion abrogated the fibrosis-memory effect, while adoptive transfer of memory T cells from fibrotic mice enhanced fibrosis in the recipients. Moreover, IL-3 production by memory CD4+ T cells was essential for aggravation of fibrosis in memory situations. In patients with systemic sclerosis, IL-3 expression by T cells was markedly increased, especially after a long disease duration accompanied by involvement of internal organs. In summary, our data identify IL-3–mediated fibrosis-memory as an important driver of progressive fibrosis.

Authors

Simone Buchtler, Antje Frühauf, Sophia Neumayer, Kathrin Schmidbauer, Yvonne Talke, Frederike Winter-Köhler, Saidou Balam, Karin Landgraf, Claudia Gebhard, Michael Rehli, Florian Volker Schlieckau, Maria Beck, Florian Günther, Martin Fleck, Kerstin Renner, Matthias Mack

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Figure 1

Evidence for long-lasting fibrosis-memory in mice with renal fibrosis.

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Evidence for long-lasting fibrosis-memory in mice with renal fibrosis. (...
(A, B, and E) Mice underwent RUUO of the right kidney from day 0–6 (first insult), were sham operated, or remained naive (Ø). Mice then underwent UUO of the left kidney from day 17 to 22 (second insult) or remained naive (Ø). (A) Quantification of collagen-1 (Col1), overall fibrosis (fibrotic area), and col1a1 mRNA expression in the left kidney on day 22. Two pooled experiments, with n = 4, naive; 8, received the second insult only; 17, sham; and 16, RUUO. (B–D) Mice underwent RUUO of the right kidney from day 0 to 6 (first insult) or remained naive (Ø). Mice then underwent UUO of the left kidney from day 11 to 16 or from day 37 to 42 (second insult). (B) Analysis of the left UUO kidney on day 16 or day 42. Two pooled experiments, with n = 14 naive; 10 day 16 UUO; and 8 day 37 UUO for immunofluorescence and qPCR, and 1 single experiment for Trichrome staining, with n = 8 received the second insult only; 6, day 11 UUO; and 8, day 37 UUO. (C) Representative images of collagen-1 immunofluorescence and Trichrome staining. (D) Quantification of infiltrating CD4+ T cells, CD8+ T cells, monocytes (Monos), and neutrophils (Neutros) in the left UUO kidneys (single experiment with n = 8 received the second insult only; 6, day 11 UUO; and 8, day 37 UUO). (E) Quantification of CD4+ tissue-resident memory (TRM) T cells in the blood, spleen, and left UUO kidneys (single experiment with n = 6 and 4). Scale bars: 100 μm. Data are represented as mean ± SEM. One-way ANOVA with multiple comparisons. *P < 0.05; **P < 0.01; ***P < 0.001.