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Blood, 28 May 2009, Vol. 113, No. 22, pp. 5650-5659. Prepublished online as a Blood First Edition Paper on April 3, 2009; DOI 10.1182/blood-2008-09-176776.
VASCULAR BIOLOGY Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution1 National Research Laboratory of Vascular Biology and Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea; 2 Laboratory of Liposome Research, Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland; 3 Department of Oral Microbiology and Immunology, Dental Research Institute, School and BK21 Program of Dentistry, Seoul National University, Seoul, Korea; 4 International Vaccine Institute, Seoul, Korea; and 5 The Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland Using a bacterial pathogen–induced acute inflammation model in the skin, we defined the roles of local lymphatic vessels and draining lymph nodes (DLNs) in antigen clearance and inflammation resolution. At the peak day of inflammation, robust expansion of lymphatic vessels and profound infiltration of CD11b+/Gr-1+ macrophages into the inflamed skin and DLN were observed. Moreover, lymph flow and inflammatory cell migration from the inflamed skin to DLNs were enhanced. Concomitantly, the expression of lymphangiogenic growth factors such as vascular endothelial growth factor C (VEGF-C), VEGF-D, and VEGF-A were significantly up-regulated in the inflamed skin, DLNs, and particularly in enriched CD11b+ macrophages from the DLNs. Depletion of macrophages, or blockade of VEGF-C/D or VEGF-A, largely attenuated these phenomena, and produced notably delayed antigen clearance and inflammation resolution. Conversely, keratin 14 (K14)–VEGF-C transgenic mice, which have dense and enlarged lymphatic vessels in the skin dermis, exhibited accelerated migration of inflammatory cells from the inflamed skin to the DLNs and faster antigen clearance and inflammation resolution. Taken together, these results indicate that VEGF-C, -D, and -A derived from the CD11b+/Gr-1+ macrophages and local inflamed tissues play a critical role in promoting antigen clearance and inflammation resolution.
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