Key Points
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Endothelial cells are major participants in and regulators of inflammatory reactions.
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Resting endothelial cells prevent coagulation, control blood flow and passage of proteins from blood into tissues, and inhibit inflammation. Production of nitric oxide (NO) has a role in these processes and inadequate production of NO is a major cause of endothelial cell dysfunction.
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Type I activation of endothelial cells mediated by G-protein coupled receptors (GPCRs) that activate G-protein αq subunits and cause endothelial cells to increase blood flow (enhancing delivery of leukocytes to the tissue), increase leakage of plasma proteins into the tissue (creating a provisional matrix to support leukocytes) and promote the binding and activation of neutrophils, encouraging their extravasation into an inflammatory site. Type I activation responses are rapid, independent of protein synthesis, and transient, spontaneously shutting off within 10–20 minutes.
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Type II activation of endothelial cells mediated by pro-inflammatory cytokines such as tumour-necrosis factor (TNF) and interleukin-1 (IL-1) also increase local blood flow, leakage of plasma proteins and recruit leukocytes. Type II activation responses depend on new gene transcription and protein translation, and are slower in onset but more sustained than type I activation responses, lasting for hours to days.
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Type-II-activated endothelial cells spontaneously evolve from a phenotype that recruits neutrophils to one that recruits monocytes and T cells. Polarizing cytokines, such as interferon-γ or IL-4 can further modify the activated endothelial cell phenotype to preferentially support T helper 1 (TH1)-cell- or TH2-cell-type inflammatory reactions, respectively.
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In chronic inflammation, endothelial cells respond to angiogenic factors, such as vascular endothelial growth factor A (VEGFA), to form new blood vessels that are required to sustain an inflammatory neo-tissue such as a pannus in rheumatoid arthritis. Endothelial cells may also respond to lymphotoxin-β to acquire characteristics of high endothelial venules and support the development of tertiary lymphoid organs.
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Many inflammatory processes display both acute and chronic changes at the same time. This may result because mediators of acute inflammation (such as TNF) contribute to the phenotypes of endothelial cells associated with chronic inflammatory and, similarly mediators of chronic inflammation (such as VEGFA) may also contribute to endothelial cell behaviours associated with acute inflammation.
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Many therapeutic agents thought to target inflammatory processes or vascular processes affect the inflammatory function of endothelial cells. Our deeper understanding of the mediators, signals and effector molecules involved in endothelial cell inflammatory functions may allow specific targeting of this cell type as a treatment for inflammatory diseases.
Abstract
Inflammation is usually analysed from the perspective of tissue-infiltrating leukocytes. Microvascular endothelial cells at a site of inflammation are both active participants in and regulators of inflammatory processes. The properties of endothelial cells change during the transition from acute to chronic inflammation and during the transition from innate to adaptive immunity. Mediators that act on endothelial cells also act on leukocytes and vice versa. Consequently, many anti-inflammatory therapies influence the behaviour of endothelial cells and vascular therapeutics influence inflammation. This Review describes the functions performed by endothelial cells at each stage of the inflammatory process, emphasizing the principal mediators and signalling pathways involved and the therapeutic implications.
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Glossary
- Ectopic lymphoid structures
-
Organized lymphocytic aggregates that form in sites of chronic inflammation. Typically, T-cell- and B-cell-rich zones are segregated, and dendritic cells (DCs), germinal centres with follicular DC (FDC) networks and specialized endothelia are present. These structures are also known as the 'tertiary lymphoid organs' and their formation is termed 'lymphoid neogenesis'.
- Lipid rafts
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Cholesterol and glycosphingolipid-rich regions of the plasma membrane that provide ordered structure to the lipid bilayer.
- Vesicular–vacuolar organelles
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A collection of caveolae-like structures, typically located near the inter-endothelial junctions, that may participate in transcytosis of plasma proteins and fluid during certain types of inflammation or in tumour vasculature. VVOs may be distinguished from true caveolae because they are found in caveolin-1 gene deficient mice, which otherwise lack endothelial caveolae.
- Angiogenesis
-
The process of the development of new blood vessels from existing blood vessels. It is frequently associated with tumour development and inflammation. In recent years, it has been appreciated that angiogenesis may be supplemented by the local recruitment of circulating endothelial progenitor cells. The formation of new blood vessels from progenitors is called vasculogenesis.
- E3 ubiquitin ligase
-
An enzyme that is required to attach the molecular tag ubiquitin to proteins. Depending on the position and number of ubiquitin molecules that are attached, the ubiquitin tag can target proteins for degradation in the proteasomal complex, create a scaffold for assembly of signalling complexes, sort them to specific subcellular compartments or modify their biological activity.
- Diapedesis
-
The last step in the leukocyte–endothelial cell adhesion cascade. This cascade includes tethering, triggering, tight adhesion and transmigration. Diapedesis is the migration of leukocytes across the endothelium, which generally occurs by squeezing through the junctions between adjacent endothelial cells, although in some settings, leukocytes have been observed to pass through transiently formed gaps in the cytoplasm of endothelial cells.
- Epitope spreading
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The de novo activation of autoreactive T cells by self-antigens that have been released after T- or B-cell-mediated bystander damage.
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Pober, J., Sessa, W. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 7, 803–815 (2007). https://doi.org/10.1038/nri2171
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DOI: https://doi.org/10.1038/nri2171
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