Myeloid-specific blockade of Notch signaling alleviates murine pulmonary fibrosis through regulating monocyte-derived Ly6c(lo)MHCII(hi) alveolar macrophages recruitment and TGF-beta secretion
Myeloid-specific blockade of Notch signaling alleviates murine pulmonary fibrosis through regulating monocyte-derived Ly6c(lo)MHCII(hi) alveolar macrophages recruitment and TGF-beta secretion
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骨髓特异性阻断 Notch 信号传导通过调节单核细胞来源的 Ly6c(lo)MHCII(hi) 肺泡巨噬细胞募集和 TGF-β 分泌减轻小鼠肺纤维化
DOI：
10.1096/fj.201903086rr
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Qin HY
中科院分区：
文献类型：
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作者：
Zhang N;Yang K;Bai J;Yi J;Gao CC;Zhao JL;Liang SQ;Wei TX;Feng L;Song LQ;Han H;Qin HY
肺内巨噬细胞（包括肺泡巨噬细胞（AM）和间质巨噬细胞（IM））以及单核细胞衍生的巨噬细胞在肺纤维化（PF）中发挥重要作用，但其差异调节机制尚不清楚。转录信号结合蛋白Jκ（RBP‐J）介导的Notch信号调节巨噬细胞发育和表型。在这里，我们使用博莱霉素诱导的纤维化模型结合髓系特异性RBP-J破坏（RBP-JcKO）小鼠，研究了PF期间巨噬细胞中Notch信号传导的作用。与对照组相比，RBP-JcKO小鼠表现出减轻的肺纤维化，表现为胶原沉积和炎症减少，以及TGF-β产生减少。FACS分析表明，减少的Ly 6cloMHCIIhiAM可能对RBP‐ JcKO小鼠中减弱的纤维形成做出主要贡献，可能是通过减少炎症因子释放和增强基质金属蛋白酶表达。在RBP-JckO小鼠中使用氯膦酸盐介导的巨噬细胞耗竭，我们证明了胚胎来源的AM在肺纤维化中的作用可以忽略不计，这得到了过继转移实验的进一步支持。此外，在CCR 2敲除背景下，未引起RBP-J缺乏对纤维发生的影响，表明Notch调节单核细胞来源的AM。共培养实验表明，由于TGF-β分泌减少，来自RBP-JcKO小鼠的单核细胞衍生AM表现出肌成纤维细胞活化减少。总之，单核细胞衍生的Ly 6cloMHCIIhiAM受RBP-J-介导的Notch信号转导的调节，在肺纤维化中发挥重要作用。
Macrophages in lung, including resident alveolar macrophages (AMs) and interstitial macrophages (IMs), and monocyte‐derived macrophages, play important roles in pulmonary fibrosis (PF), but mechanisms underlying their differential regulation remain unclear. Recombination signal‐binding protein Jκ (RBP‐J)‐mediated Notch signaling regulates macrophage development and phenotype. Here, using bleomycin‐induced fibrosis model combined with myeloid‐specific RBP‐J disruption (RBP‐JcKO) mouse, we investigated the role of Notch signaling in macrophages during PF. Compared with the control, RBP‐JcKOmice exhibited alleviated lung fibrosis as manifested by reduced collagen deposition and inflammation, and decreased TGF‐β production. FACS analysis suggested that decreased Ly6cloMHCIIhiAMs might make the major contribution to attenuated fibrogenesis in RBP‐JcKOmice, probably by reduced inflammatory factor release and enhanced matrix metalloproteinases expression. Using clodronate‐mediated macrophage depletion in RBP‐JckOmice, we demonstrated that embryonic‐derived AMs play negligible role in lung fibrosis, which was further supported by adoptive transfer experiments. Moreover, on CCR2 knockout background, the effect of RBP‐J deficiency on fibrogenesis was not elicited, suggesting that Notch regulated monocyte‐derived AMs. Co‐culture experiment showed that monocyte‐derived AMs from RBP‐JcKOmice exhibit reduced myofibroblast activation due to decreased TGF‐β secretion. In conclusion, monocyte‐derived Ly6cloMHCIIhiAMs, which are regulated by RBP‐J‐mediated Notch signaling, play an essential role in lung fibrosis.