Lung vascular endothelial growth factor expression induces local myeloid dendritic cell activation.
We previously demonstrated that vascular endothelial growth factor (VEGF) expression in the murine lung increases local CD11c+MHCII+ DC number and activation. In this study, employing a multicolor flow cytometry, we report increases in both myeloid (mDC) and plasmacytoid (pDC) DC in the lungs of VEGF transgenic (tg) compared to WT mice. Lung pDC from VEGF tg mice exhibited higher levels of activation with increased expression of MHCII and costimulatory molecules. As VEGF tg mice display an asthma-like phenotype and lung mDC play a critical role in asthmatic setting, studies were undertaken to further characterize murine lung mDC. Evaluations of sorted mDC from VEGF tg lungs demonstrated a selective upregulation of cathepsin K, MMP-8, -9, -12, and -14, and chemokine receptors as compared to those obtained from WT control mice. They also had increased VEGFR2 but downregulated VEGFR1 expression. Analysis of chemokine and regulatory cytokine expression in these cells showed an upregulation of macrophage chemotactic protein-3 (MCP-3), thymus-expressed chemokine (TECK), secondary lymphoid organ chemokine (SLC), macrophage-derived chemokine (MDC), IL-1beta, IL-6, IL-12 and IL-13. The antigen (Ag) OVA-FITC uptake by lung DC and the migration of Ag-loaded DC to local lymph nodes were significantly increased in VEGF tg mice compared to WT mice. Thus, VEGF may predispose the lung to inflammation and/or repair by activating local DC. It regulates lung mDC expression of innate immunity effector molecules. The data presented here demonstrate how lung VEGF expression functionally affects local mDC for the transition from the innate response to a Th2-type inflammatory response.
Chapoval
Svetlana P
SP
Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, 441-C TAC, New Haven, CT 06520-8057, USA. schapoval@som.umaryland.edu
Lee
Chun Geun
CG
Tang
Chuyan
C
Keegan
Achsah D
AD
Cohn
Lauren
L
Bottomly
Kim
K
Elias
Jack A
JA
D000818:Animals; D000941:Antigens / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D002403:Cathepsins / Q000235:genetics; D002465:Cell Movement / Q000276:immunology; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D037181:Lectins, C-Type / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology; D020782:Matrix Metalloproteinases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D000941:Antigens; D015703:Antigens, CD; D039521:CD11c Antigen; D018925:Chemokines; D016207:Cytokines; C093569:DEC-205 receptor; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D010047:Ovalbumin; D040262:Receptors, Vascular Endothelial Growth Factor; D002403:Cathepsins; D020782:Matrix Metalloproteinases