Siglec-F–expressing neutrophils are essential for creating a profibrotic microenvironment in renal fibrosis
Seungwon Ryu, … , Seung Hee Yang, Hye Young Kim
Seungwon Ryu, … , Seung Hee Yang, Hye Young Kim
Published April 28, 2022
Citation Information: J Clin Invest. 2022;132(12):e156876. https://doi.org/10.1172/JCI156876.
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Research Article Immunology Nephrology Article has an altmetric score of 1

Siglec-F–expressing neutrophils are essential for creating a profibrotic microenvironment in renal fibrosis

Abstract

The roles of neutrophils in renal inflammation are currently unclear. On examining these cells in the unilateral ureteral obstruction murine model of chronic kidney disease, we found that the injured kidney bore a large and rapidly expanding population of neutrophils that expressed the eosinophil marker Siglec-F. We first verified that these cells were neutrophils. Siglec-F+ neutrophils were recently detected in several studies in other disease contexts. We then showed that a) these cells were derived from conventional neutrophils in the renal vasculature by TGF-β1 and GM-CSF; b) they differed from their parent cells by more frequent hypersegmentation, higher expression of profibrotic inflammatory cytokines, and notably, expression of collagen 1; and c) their depletion reduced collagen deposition and disease progression, but adoptive transfer increased renal fibrosis. These findings have thus unveiled a subtype of neutrophils that participate in renal fibrosis and a potentially new therapeutic target in chronic kidney disease.

Authors

Seungwon Ryu, Jae Woo Shin, Soie Kwon, Jiwon Lee, Yong Chul Kim, Yoe-Sik Bae, Yong-Soo Bae, Dong Ki Kim, Yon Su Kim, Seung Hee Yang, Hye Young Kim

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Figure 2

Siglec-F–expressing neutrophils accumulate as fibrosis progresses.

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Siglec-F–expressing neutrophils accumulate as fibrosis progresses. (A) F...
(A) Flow cytometric analysis of the Siglec-F and Ly-6G expression on CD11b+ leukocytes in UUO kidneys. Left, conventional neutrophils (Siglec-F–Ly-6G+). Right, Siglec-F+Ly-6G+ cells. (B) Flow cytometric analysis of the expression of neutrophil (Ly-6G and Siglec-E) and eosinophil (Siglec-F and CCR3) markers on the conventional eosinophils (Siglec-F+Ly-6G–), the conventional neutrophils (Siglec-F–Ly-6G+), and the Siglec-F+Ly-6G+ cells in the UUO kidney on day 14. (C) Evaluation of the morphology of the conventional neutrophils and the Siglec-F+Ly-6G+ cells on day 14 by sorting and staining them with Diff-Quik and counting the numbers of primitive, mature, and hypersegmented neutrophils; scale bar: 20 μm. (D and E) Mice were treated with the recombinant IL-33 (250 ng) for 4 consecutive days starting on the day of UUO surgery (D), and the frequencies of conventional neutrophils, eosinophils, and Siglec-F+Ly-6G+ cells on day 14 were determined by flow cytometry (E). (F and G) Eosinophil-deficient ΔdblGATA mice (BALB/c background) were subjected to UUO (F), and the conventional neutrophil and Siglec-F+Ly-6G+ cell frequencies in the kidney on day 14 were determined by flow cytometry (G). All results are shown as mean ± SEM, and statistical analysis was performed using 1-way ANOVA (A, B, and E) or Mann-Whitney U test (G). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; n = 4–5 mice in each group.