Vascular endothelial growth factor-A (VEGF-A) expression is up-regulated in several inflammatory diseases including psoriasis, delayed-type hypersensitivity (DTH) reactions, and rheumatoid arthritis. To directly characterize the biologic function of VEGF-A in inflammation, we evaluated experimental DTH reactions induced in the ear skin of transgenic mice that overexpress VEGF-A specifically in the epidermis. VEGF-A transgenic mice underwent a significantly increased inflammatory response that persisted for more than 1 month, whereas inflammation returned to baseline levels within 7 days in wild-type mice. Inflammatory lesions in VEGF-A transgenic mice closely resembled human psoriasis and were characterized by epidermal hyperplasia, impaired epidermal differentiation, and accumulation of dermal CD4 ؉ T-lymphocytes and epidermal CD8 ؉ lymphocytes. Surprisingly, VEGF-A also promoted lymphatic vessel proliferation and enlargement, which might contribute to the increased inflammatory response, as lymphatic vessel enlargement was also detected in human psoriatic skin lesions. Combined systemic treatment with blocking antibodies against VEGF receptor-1 (VEGFR-1) and VEGFR-2 potently inhibited inflammation and also decreased lymphatic vessel size. Together, these findings reveal a central role of VEGF-A in promoting lymphatic enlargement, vascular hyperpermeability, and leukocyte recruitment, thereby leading to persistent chronic inflammation. They also indicate that inhibition of VEGF-A bioactivity might be a new approach to anti-inflammatory therapy. IntroductionVascular endothelial growth factor-A (VEGF-A) is a homodimeric heparin-binding glycoprotein that occurs in at least 4 isoforms of 121, 165, 189, and 201 amino acids, as a result of alternative splicing (corresponding murine proteins are one amino acid shorter). VEGF-A binds to the 2 type III receptor tyrosine kinases VEGF receptor-1 (VEGFR-1, Flt-1) and VEGFR-2 (KDR or Flk-1), which are primarily expressed by vascular endothelial cells. 1,2 VEGF-A165 also binds to the nonkinase receptors neuropilin 1 and 2. 3 VEGF-A stimulates endothelial cell migration, proliferation, and survival in vitro and promotes microvascular permeability and angiogenesis in vivo. 4,5 Previous studies have revealed that VEGF-A expression by epidermal keratinocytes and endothelial expression of VEGF receptors are up-regulated in several inflammatory conditions including psoriasis, 6 delayed-type hypersensitivity reactions, 7 and bullous diseases. 8 However, the biologic importance of VEGF in the pathogenesis of chronic inflammation has remained unclear.The lymphatic vascular system is composed of a network of thin-walled capillaries that drain protein-rich lymph from the extracellular space and thereby maintain normal tissue pressure. 9 Moreover, lymphatic vessels play an important role in the afferent phase of the immune response. 10 Little is known about the role of the lymphatic vascular system in the control of chronic inflammation, however, due to a lack of reliable markers and t...

Cross-presentation of IgG-containing immune complexes (ICs) is an important means by which dendritic cells (DCs) activate CD8 + T cells, yet it proceeds by an incompletely understood mechanism. We show that monocyte-derived CD8 − CD11b+ DCs require the neonatal Fc receptor for IgG (FcRn) to conduct cross-presentation of IgG ICs. Consequently, in the absence of FcRn, Fcγ receptor (FcγR)-mediated antigen uptake fails to initiate cross-presentation. FcRn is shown to regulate the intracellular sorting of IgG ICs to the proper destination for such cross-presentation to occur. We demonstrate that FcRn traps antigen and protects it from degradation within an acidic loading compartment in association with the rapid recruitment of key components of the phagosome-to-cytosol crosspresentation machinery. This unique mechanism thus enables cross-presentation to evolve from an atypically acidic loading compartment. FcRn-driven cross-presentation is further shown to control cross-priming of CD8 + T-cell responses in vivo such that during chronic inflammation, FcRn deficiency results in inadequate induction of CD8 + T cells. These studies thus demonstrate that crosspresentation in CD8 − CD11b+ DCs requires a two-step mechanism that involves FcγR-mediated internalization and FcRn-directed intracellular sorting of IgG ICs. Given the centrality of FcRn in controlling cross-presentation, these studies lay the foundation for a unique means to therapeutically manipulate CD8 + T-cell responses.

SununarySuggestive evidence indicates that immunoglobulin E (IgE)-dependent activation of mononuclear phagocytes plays an important pathogenic role in allergic tissue inflammation. Prevailing opinion holds that low affinity IgE receptors are the relevant IgE-binding structures on monocytes/ macrophages and that functional events occurring after cross-linking of membrane-bound IgE on these cells are mediated by these receptors. Here we demonstrate that Ix-ripheral blood monocytes can bind monomeric IgE via the high affinity IgE receptor (FceRI) and that FceRI expression on these ceils is upregulated in atopic persons. Further, we demonstrate that, upon monocyte adherence to substrate, bridging of monocyte FcdLl is followed by cell activation. We propose that direct interaction of multivalent allergen with Fc~RI+-bound IgE on mononuclear phagocytes results in cell signaling via Fcd~I and that the biological consequences of this event may critically influence the outcome of allergic reactions.