Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, 19104, USA.
Department of Pathology, University of California, San Francisco, CA, 94143, USA.
Mucosal Immunol. 2019 Jan;12(1):64-76. doi: 10.1038/s41385-018-0096-2. Epub 2018 Oct 18.
Coordinated efforts between macrophages and epithelia are considered essential for wound healing, but the macrophage-derived molecules responsible for repair are poorly defined. This work demonstrates that lung macrophages rely upon Trefoil factor 2 to promote epithelial proliferation following damage caused by sterile wounding, Nippostrongylus brasiliensis or Bleomycin sulfate. Unexpectedly, the presence of T, B, or ILC populations was not essential for macrophage-driven repair. Instead, conditional deletion of TFF2 in myeloid-restricted CD11c TFF2 mice exacerbated lung pathology and reduced the proliferative expansion of CD45 EpCAM pro-SPC alveolar type 2 cells. TFF2 deficient macrophages had reduced expression of the Wnt genes Wnt4 and Wnt16 and reconstitution of hookworm-infected CD11c TFF2 mice with rWnt4 and rWnt16 restored the proliferative defect in lung epithelia post-injury. These data reveal a previously unrecognized mechanism wherein lung myeloid phagocytes utilize a TFF2/Wnt axis as a mechanism that drives epithelial proliferation following lung injury.
巨噬细胞和上皮细胞之间的协调作用被认为对伤口愈合至关重要，但负责修复的巨噬细胞衍生分子的定义还很不清楚。这项工作表明，肺巨噬细胞依赖三叶因子 2（Trefoil factor 2，TFF2）来促进无菌性损伤、巴西旋毛虫或博来霉素硫酸盐引起的上皮细胞增殖。出乎意料的是，T、B 或 ILC 群体的存在对于巨噬细胞驱动的修复并不是必需的。相反，髓系限制性 CD11c TFF2 条件性敲除小鼠中 TFF2 的缺失加剧了肺病理学并减少了 CD45 EpCAM pro-SPC 肺泡 II 型细胞的增殖扩张。TFF2 缺陷型巨噬细胞中 Wnt 基因 Wnt4 和 Wnt16 的表达降低，而用 rWnt4 和 rWnt16 重建感染钩虫的 CD11c TFF2 小鼠则恢复了损伤后肺上皮细胞的增殖缺陷。这些数据揭示了一个以前未被认识的机制，即肺髓系吞噬细胞利用 TFF2/Wnt 轴作为一种机制，在肺损伤后驱动上皮细胞增殖。
