Abstract
Toll-like receptors (TLRs) are known as pattern-recognition receptors related to the Toll protein of Drosophila. After recognition of pathogen-associated molecular patterns of microbial origin, the TLRs alert the immune system, and initiate innate and adaptive immune responses. The TLR system, though, is not confined solely to the leukocyte-mediated immune defense against exogenous pathogens. Besides myeloid cells, TLR expression has been reported in multiple tissues and cell types, including epithelial and endothelial cells. Moreover, despite the microbial patterns that are commonly accepted as TLR ligands, there is increasing evidence that TLRs also recognize host-derived molecules. In this regard, recent studies point to an involvement of TLRs in various chronic inflammatory disorders and cardiovascular diseases, including atherosclerosis, rheumatoid arthritis, systemic lupus erythematosus, and even cancer. A common feature of these disorders is an enhanced so-called inflammation-induced angiogenesis. However, inflammation-induced angiogenesis is not solely a key component of pathogen defense during acute infection or chronic inflammatory disorders, but also plays a critical role in repair mechanisms, e.g., wound healing and subsequent tissue regeneration. Interestingly, the latest research could coincidentally demonstrate that TLR activation promotes angiogenesis in various inflammatory settings in response to both exogenous and endogenous ligands, although the precise mode of action of TLRs in this context still remains ambiguous. The objective of this review is to present evidence for the implication of TLRs in angiogenesis during physiological and pathophysiological processes, and the potential clinical relevance for new treatment regimes involving TLR modulation.
Highlights
The most promising future therapeutic approach is the application of specific TLR agonists in damaged ischemic or hypoxic tissues in order to promote angiogenesis and subsequent tissue regeneration, especially when the tissue damage is not initiated or accompanied by severe infection
We recently reported that the proangiogenic properties of MALP-2 critically depended on the induction of the growth factor GM-CSF in endothelial cells and monocytes[43]
Modulation of TLR activity could be used for different future therapeutic concepts; on the one hand, to inhibit pathological tumor angiogenesis to limit tumor growth and on the other hand, to promote physiological angiogenesis for tissue regeneration
Summary
Inflammation is not solely a key component of pathogen defense during infection; it plays a critical role in repair mechanisms, e.g., wound healing and subsequent tissue regeneration. Cytokines and growth factors released at the site of injury are essential for the repair process[30] In this regard, angiogenesis, the re-establishment of a capillary network by endothelial cells, is mainly initiated and maintained by the major proangiogenic factor VEGF. Are recruited to sites of wound healing, partly by the action of the proangiogenic factors such as VEGF All these cells in turn release proangiogenic factors such as VEGF, bFGF, TGF-β, PDGF, tumor necrosis factor (TNF)- , insulin-like growth factor (IGF)-1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, IL-8, and many more. There is a significant number of publications showing that several TLR agonists are able to induce the expression and secretion of angiogenic factors from different cell types in vitro The majority of these studies remains rather descriptive in this context and is very much focused on LPS and VEGF. Only few data document a direct involvement of TLRs in angiogenesis, both in physiological and in pathophysiological settings
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