Newcastle Fibrosis Research Group and.
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
JCI Insight. 2020 Feb 27;5(4):125937. doi: 10.1172/jci.insight.125937.
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.
中性粒细胞是创伤愈合早期最丰富的炎症细胞，在创伤修复和纤维化中发挥重要作用。甲酰肽受体 1（FPR-1）在中性粒细胞上大量表达，并已被证明调节其功能，但 FPR-1 在纤维化中的重要性仍未得到明确界定。FPR-1 缺陷（fpr1-/-）小鼠对博来霉素诱导的肺纤维化具有保护作用，但正常发生肾和肝纤维化。从机制上讲，我们观察到 fpr1-/-小鼠的肺部无法有效招募中性粒细胞，而中性粒细胞在肝脏和肾脏中的招募不受影响。通过过继转移模型，我们证明了 fpr1-/-中性粒细胞向肺部的招募缺陷是内在的，因为 C57BL/6 中性粒细胞在 fpr1-/-小鼠的受损肺部正常招募。最后，中性粒细胞耗竭的 C57BL/6 小鼠对肺纤维化具有保护作用。总之，FPR-1 和 FPR-1 配体是有效招募中性粒细胞到受损肺部所必需的。无法招募中性粒细胞或耗尽中性粒细胞可预防肺纤维化。
