Toll-Like Receptor-Linked Signal Transduction in Angiogenesis
Mammalian Toll-like receptors (TLRs) represent pattern recognition receptors of the immune system and are related to the Toll protein of Drosophila. Pathogen-associated molecular patterns (PAMPs) of microbial and viral origin bind to TLRs and initiate the
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Toll-Like Receptor-Linked Signal Transduction in Angiogenesis Karsten Grote, Harald Schütt, and Bernhard Schieffer
Abstract Mammalian Toll-like receptors (TLRs) represent pattern recognition receptors of the immune system and are related to the Toll protein of Drosophila. Pathogen-associated molecular patterns (PAMPs) of microbial and viral origin bind to TLRs and initiate the innate and adaptive immune response. However, TLRs are not solely found on cells of the immune system but also on nonmyeloid cells in various tissues, e.g., on vascular cells. In addition to PAMPs, there is increasing evidence that TLRs also recognize endogenous ligands. Recent studies demonstrate the contribution of distinct TLRs in different inflammatory disorders such as cardiovascular diseases, rheumatoid arthritis, systemic lupus erythematosus, and cancer. Many of these disorders are characterized by enhanced angiogenesis which is mainly trigged by inflammation. However, this inflammation-induced angiogenesis is not only important for pathogen defense during acute infection or chronic inflammatory disorders but as well involved in regenerative processes during wound healing and tissue repair. There is cumulative evidence that TLR activation by exogenous as well as endogenous ligands especially contributes to angiogenic process in this scenario. The present chapter will summarize the current understanding of TLRlinked signal transduction in angiogenesis during inflammatory processes with future prospects for pro- or antiangiogenic therapy. Keywords Toll-like receptors • Angiogenesis • Pathogen-associated pattern • Leucine-rich repeats • Damage-associated molecular patterns • Inflammation
K. Grote (*) • H. Schütt • B. Schieffer Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany e-mail: [email protected]
J.L. Mehta and N.S. Dhalla (eds.), Biochemical Basis and Therapeutic Implications of Angiogenesis, Advances in Biochemistry in Health and Disease 6, DOI 10.1007/978-1-4614-5857-9_9, © Springer Science+Business Media New York 2013
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Introduction: Toll! Everything Started in Drosophila
A group of maternal effect genes are necessary for the embryo patterning of the fruit fly Drosophila melanogaster including the Toll gene. Lack of function experiments revealed that the Toll gene product provides the source for a morphogen gradient in the dorsal–ventral axis of the Drosophila embryo [1, 2]. Mutants in this gene were originally identified in 1985 by the group of Christiane Nüsslein-Volhard at the Max-Planck-Institute in Tübingen/Germany. The name of the gene derives from her exclamation “Das ist ja toll!,” which translates as “That’s amazing!” during microscopic observation of the drosophila mutants. Three years later, the Toll gene of Drosophila was cloned in the lab of Kathryn Anderson, the first author of the initial studies [3]. In 1992, Christiane Nüsslein-Volhard was awarded with the Nobel Prize for her groundbreaking research. Late
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