| First Author | Outtz HH | Year | 2010 |
| Journal | J Immunol | Volume | 185 |
| Issue | 7 | Pages | 4363-73 |
| PubMed ID | 20739676 | Mgi Jnum | J:164219 |
| Mgi Id | MGI:4830916 | Doi | 10.4049/jimmunol.1000720 |
| Citation | Outtz HH, et al. (2010) Notch1 deficiency results in decreased inflammation during wound healing and regulates vascular endothelial growth factor receptor-1 and inflammatory cytokine expression in macrophages. J Immunol 185(7):4363-73 |
| abstractText | We investigated whether Notch signaling plays a role in regulating macrophage responses to inflammation. In a wound healing assay, macrophage recruitment was decreased in Notch1(+/-) mice, and the wounds were characterized by decreased TNF-alpha expression. As wound healing progressed, Notch1(+/-) wounds had increased vascularization and collagen deposition compared with wild-type wounds. In mice with myeloid-specific Notch1 deletion, wounds had decreased macrophage recruitment as well as decreased TNF-alpha expression, indicating the specific role of Notch1 in the inflammatory response in these cells. In vitro, we found that vascular endothelial growth factor receptor-1 (VEGFR-1) was upregulated in macrophages in response to LPS/IFN-gamma and that this upregulation depended on Notch signaling. Furthermore, macrophages from Notch1(+/-) mice had decreased expression of VEGFR-1 compared with macrophages from wild-type mice, whereas VEGFR-1 expression in Notch4(-/-) macrophages was normal. Inhibition of Notch signaling decreased induction of the inflammatory cytokines IL-6, IL-12, CXCL10, MCP-1, monokine induced by IFN-gamma, and TNF-alpha in macrophages in response to LPS/IFN-gamma. Additionally, macrophages from Notch1(+/-) mice demonstrated decreased induction of IL-6, IL-12, and TNF-alpha in response to stimulation compared with wild-type mice. Thus, both pharmacological inhibition of Notch and genetic analysis demonstrate that Notch1 regulates VEGFR-1 and cytokine expression in macrophages. We have also established that Notch1 is important for the inflammatory response during wound healing in mice. |
