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FPR-1 is an important regulator of neutrophil recruitment and a tissue-specific driver of pulmonary fibrosis
Jack Leslie, … , Derek A. Mann, Lee A. Borthwick
Jack Leslie, … , Derek A. Mann, Lee A. Borthwick
Published February 27, 2020
Citation Information: JCI Insight. 2020;5(4):e125937. https://doi.org/10.1172/jci.insight.125937.
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Research Article Cell biology Immunology

FPR-1 is an important regulator of neutrophil recruitment and a tissue-specific driver of pulmonary fibrosis

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Abstract

Neutrophils are the most abundant inflammatory cells at the earliest stages of wound healing and play important roles in wound repair and fibrosis. Formyl peptide receptor 1 (FPR-1) is abundantly expressed on neutrophils and has been shown to regulate their function, yet the importance of FPR-1 in fibrosis remains ill defined. FPR-1–deficient (fpr1–/–) mice were protected from bleomycin-induced pulmonary fibrosis but developed renal and hepatic fibrosis normally. Mechanistically, we observed a failure to effectively recruit neutrophils to the lungs of fpr1–/– mice, whereas neutrophil recruitment was unaffected in the liver and kidney. Using an adoptive transfer model we demonstrated that the defect in neutrophil recruitment to the lung was intrinsic to the fpr1–/– neutrophils, as C57BL/6 neutrophils were recruited normally to the damaged lung in fpr1–/– mice. Finally, C57BL/6 mice in which neutrophils had been depleted were protected from pulmonary fibrosis. In conclusion, FPR-1 and FPR-1 ligands are required for effective neutrophil recruitment to the damaged lung. Failure to recruit neutrophils or depletion of neutrophils protects from pulmonary fibrosis.

Authors

Jack Leslie, Ben J.M. Millar, Alicia del Carpio Pons, Rachel A. Burgoyne, Joseph D. Frost, Ben S. Barksby, Saimir Luli, Jon Scott, A. John Simpson, Jack Gauldie, Lynne A. Murray, Donna K. Finch, Alan M. Carruthers, John Ferguson, Matthew A. Sleeman, David Rider, Rachel Howarth, Christopher Fox, Fiona Oakley, Andrew J. Fisher, Derek A. Mann, Lee A. Borthwick

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Figure 6

fpr1–/– mice are not protected from fibrosis in the unilateral ureteral obstruction model of kidney injury.

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fpr1–/– mice are not protected from fibrosis in the unilateral ureteral...
(A) The left kidney of C57BL/6 and fpr1–/– mice was obstructed by ligation of the corresponding ureter. The right kidney underwent the same surgical procedure without ligation. Mice were killed on days 5 and 12 after surgery and kidney tissue harvested. Number of (B) CD3+, (C) NIMP+, and (D) CD68+ cells per field (original magnification, ×20). Data represent the mean value of n = 20 randomly selected, nonoverlapping fields per mouse. Representative (E) Picrosirius red–stained and (G) α-smooth muscle actin–stained (αSMA-stained) kidney tissue. Percentage area positive of (F) Picrosirius red and (H) αSMA staining. Data represent the mean value of n = 20 randomly selected, nonoverlapping fields (original magnification, ×10). (I) Interstitial expansion and (J) tubular dilation as a percentage of grid intersections (excluding glomeruli) overlaying interstitial areas and tubular lumine. Data represent the mean value of n = 20 randomly selected, nonoverlapping fields (original magnification, ×20). n = 6–7 mice per group. No significant difference was seen between the right kidneys of C57BL/6 and fpr1–/– mice, and therefore mice were pooled and presented as mean (red-hashed line). Data were analyzed using a Mann-Whitney U test and presented as box-and-whisker plots. P > 0.05.

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