Inflammation; Lymphatic vessels; Lymphatic function; Adaptive immunity; VEGF-A; ALCAM
Aebischer David, Willrodt Ann-Helen, Halin Cornelia (2014), Oxazolone-induced contact hypersensitivity reduces lymphatic drainage but enhances the induction of adaptive immunity., in PloS one
, 9(6), 99297-99297.
Aebischer David, Iolyeva Maria, Halin Cornelia (2014), The inflammatory response of lymphatic endothelium., in Angiogenesis
, 17(2), 383-93.
Russo Erica, Nitschké Maximilian, Halin Cornelia (2013), Dendritic cell interactions with lymphatic endothelium., in Lymphatic research and biology
, 11(3), 172-82.
Iolyeva Maria, Aebischer David, Proulx Steven T, Willrodt Ann-Helen, Ecoiffier Tatiana, Häner Simone, Bouchaud Grégory, Krieg Carsten, Onder Lucas, Ludewig Burkhard, Santambrogio Laura, Boyman Onur, Chen Lu, Finke Daniela, Halin Cornelia (2013), Interleukin-7 is produced by afferent lymphatic vessels and supports lymphatic drainage., in Blood
, 122(13), 2271-81.
Iolyeva Maria, Karaman Sinem, Willrodt Ann-Helen, Weingartner Stephanie, Vigl Benjamin, Halin Cornelia (2013), Novel role for ALCAM in lymphatic network formation and function., in FASEB journal : official publication of the Federation of American Societies for Experimental Biolog
, 27(3), 978-90.
Vranova Martina, Halin Cornelia, Lymphatic vessels in inflammation, in Immunology
Background:Chronic inflammation is accompanied by profound changes in lymphatic vessels, such as the upregulation of adhesion molecules and chemokines, the onset of lymphangiogenesis and the induction of lymphatic vessel remodeling. The significance of most of these inflammation-induced changes is presently not well understood. In particular, it is unclear how chronic inflammation affects lymphatic vessel function, most importantly, the migration of dendritic cells (DCs) and the transport of tissue fluids to draining lymph nodes (dLNs). Since the induction of adaptive immunity in dLNs is tightly linked to the functionality of the lymphatic system, it is also largely unknown how chronic inflammation affects immune function in dLNs and thereby impacts the course of the inflammatory and/or autoimmune response. Specific Aims:With the proposed research we seek to study how acute and chronic skin inflammation affect the induction of adaptive T cell immunity in dLNs. In specific, we plan to address what impact psoriasis-like skin inflammation has on lymphatic vessel function, namely on DC migration and fluid / inflammatory mediator transport to dLNs. Furthermore, we seek to study how chronic inflammation affects T cell activation and T helper cell differentiation in dLNs. In this context, a further aim of our research is to investigate, whether VEGF-A, which is upregulated in inflamed skin and skin-draining LNs, affects T cell priming and T helper cell differentiation. Finally, we plan to study the involvement of a selected, inflammation-induced adhesion molecule, namely ALCAM (CD166), in inflammation-induced lymphangiogenesis and in DC migration to dLNs. Experimental Design and Methods:We will make use of two mouse models of the inflammatory skin disease psoriasis, namely, contact hypersensitivity-induced skin inflammation in K14-VEGF-A tg mice and skin inflammation induced in wild-type mice by repeated topical application of imiquimod. These models will be used to study the effects of inflammation on DC migration, fluid drainage and on the induction of adaptive T cell immunity. Inflammation-induced changes in the lymphatic vasculature, in leukocyte composition and cytokine levels in the skin and dLNs will be analyzed by FACS, whole-mount immunofluorescence, ELISA or gene expression profiling of ex vivo isolated cells. Furthermore, T cell receptor transgenic mice will be used to study the effect of inflammation and of inflammation-induced VEGF-A on T cell activation and polarization in vivo and in vitro (in combination with VEGF-A / VEGFR blocking antibodies or VEGFR tyrosine kinase inhibitors). Furthermore, in vitro and in vivo assays involving blocking antibodies and knockout mice will be used to study the involvement of ALCAM in inflammation-induced lymphangiogenesis and in DC migration. Expected Value of the Proposed Project:The project will shed light on the functional significance of inflammation-induced changes in the lymphatic vessel network, namely, on their impact on DC migration, antigen drainage and on the initiation of adaptive T cell immunity in dLNs. Our experiments will also help to better understand how chronic skin inflammation affects T helper cell activation and differentiation and thereby shapes the course of the immune response. Furthermore, the proposed experiments will help to expand our mechanistic understanding of the importance of VEGF-A and VEGFR signaling in immunity and inflammation. Given that VEGF-A and VEGFRs are emerging as new targets for anti-inflammatory therapies, such knowledge may be valuable for anticipating the therapeutic benefit as well as potential side effects of such treatments.