| First Author | Min JH | Year | 2016 |
| Journal | PLoS One | Volume | 11 |
| Issue | 2 | Pages | e0147846 |
| PubMed ID | 26828208 | Mgi Jnum | J:249315 |
| Mgi Id | MGI:6093109 | Doi | 10.1371/journal.pone.0147846 |
| Citation | Min JH, et al. (2016) Activation of Dll4/Notch Signaling and Hypoxia-Inducible Factor-1 Alpha Facilitates Lymphangiogenesis in Lacrimal Glands in Dry Eye. PLoS One 11(2):e0147846 |
| abstractText | PURPOSE: By using hypoxia-inducible factor-1 alpha conditional knockout (HIF-1alpha CKO) mice and a dry eye (DE) mouse model, we aimed to determine the role played by delta-like ligand 4 (Dll4)/Notch signaling and HIF-1alpha in the lymphangiogenesis of lacrimal glands (LGs). METHODS: C57BL/6 mice were housed in a controlled-environment chamber for DE induction. During DE induction, the expression level of Dll4/Notch signaling and lymphangiogenesis in LGs was measured by quantitative RT-PCR, immunoblot, and immunofluorescence staining. Next, lymphangiogenesis was measured after Dll4/Notch signal inhibition by anti-Dll4 antibody or gamma-secretase inhibitor. Using HIF-1alpha CKO mice, the expression of Dll4/Notch signaling and lymphangiogenesis in LGs of DE-induced HIF-1alpha CKO mice were assessed. Additionally, the infiltration of CD45+ cells in LGs was assessed by immunohistochemical (IHC) staining and flow cytometry for each condition. RESULTS: DE significantly upregulated Dll4/Notch and lymphangiogenesis in LGs. Inhibition of Dll4/Notch significantly suppressed lymphangiogenesis in LGs. Compared to wild-type (WT) mice, DE induced HIF-1alpha CKO mice showed markedly low levels of Dll4/Notch and lymphangiogenesis. Inhibition of lymphangiogenesis by Dll4/Notch suppression resulted in increased CD45+ cell infiltration in LGs. Likewise, CD45+ cells infiltrated more in the LGs of HIF-1alpha CKO DE mice than in non-DE HIF-1alpha CKO mice. CONCLUSIONS: Dll4/Notch signaling and HIF-1alpha are closely related to lymphangiogenesis in DE-induced LGs. Lymphangiogenesis stimulated by Dll4/Notch and HIF-1alpha may play a role in protecting LGs from DE-induced inflammation by aiding the clearance of immune cells from LGs. |
