| First Author | Zhang N | Year | 2020 |
| Journal | FASEB J | Volume | 34 |
| Issue | 8 | Pages | 11168-11184 |
| PubMed ID | 32638441 | Mgi Jnum | J:307670 |
| Mgi Id | MGI:6720652 | Doi | 10.1096/fj.201903086RR |
| Citation | Zhang N, et al. (2020) 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. FASEB J 34(8):11168-11184 |
| abstractText | 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 Jkappa (RBP-J)-mediated Notch signaling regulates macrophage development and phenotype. Here, using bleomycin-induced fibrosis model combined with myeloid-specific RBP-J disruption (RBP-J(cKO) ) mouse, we investigated the role of Notch signaling in macrophages during PF. Compared with the control, RBP-J(cKO) mice exhibited alleviated lung fibrosis as manifested by reduced collagen deposition and inflammation, and decreased TGF-beta production. FACS analysis suggested that decreased Ly6c(lo) MHCII(hi) AMs might make the major contribution to attenuated fibrogenesis in RBP-J(cKO) mice, probably by reduced inflammatory factor release and enhanced matrix metalloproteinases expression. Using clodronate-mediated macrophage depletion in RBP-J(ckO) mice, 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-J(cKO) mice exhibit reduced myofibroblast activation due to decreased TGF-beta secretion. In conclusion, monocyte-derived Ly6c(lo) MHCII(hi) AMs, which are regulated by RBP-J-mediated Notch signaling, play an essential role in lung fibrosis. |
