Endothelial Cells: Immunological Aspects

Abstract

Strategically located at the interface between blood and the extravascular space, the endothelium is a highly specialised cellular system, which plays a key role in physiological processes such as blood supply, nutrient delivery, metabolic homeostasis and immune cell trafficking, as well as pathological processes such as inflammation. Endothelial cells represent a highly heterogeneous population of cells with the ability to interact with and modulate the function of immune cells. These cells regulate the traffic and functions of leucocytes by expressing adhesion molecules and cytokines in a regulated way. The ability of endothelial cells to compartmentalise memory T‐cell responses via organ‐selective expression of homing receptor ligands and to recruit antigen‐specific T cells into inflammatory sites by displaying cognate major histocompatibility complex–peptide complexes contributes a new dimension to the central role played by endothelium in the regulation of immune responses.

Key Concepts

  • Endothelial cells are not just an inert barrier between the blood and parenchyma.
  • The endothelial cell orchestrates cellular processes key to the inflammatory reaction.
  • A regulated use of different adhesion molecules and chemokines guides tissue‐specific leucocyte extravasation.
  • Especially, microvascular endothelial cells can act as antigen‐presenting cells, leading to T lymphocyte extravasation.
  • Endothelial cells are both targets for and a source of cytokines – soluble polypeptides acting as mediators of communication with leucocytes and other cells.
  • Vasculature senescence plays an active role in promoting an inflammatory response.

Keywords: cytokines; endothelial cells; adhesion molecules; inflammation; chemokines; homing receptors; antigen presentation; transendothelial migration; immunoregulation; senescence

Figure 1. The leucocyte adhesion cascade. The emigration of circulating leucocytes is tightly regulated by the sequential action of molecular signals and adhesion molecules. Leucocyte tethering and rolling along inflamed endothelium are initiated by selectins (such as P‐selectin and E‐selectin). Rolling slows down circulating leucocytes, bringing them into close proximity with EC and allowing binding of chemokines on inflamed endothelium to their specific chemokine receptors on leucocytes.
Figure 2. Cytokine and bacterial product receptors expressed by endothelial cells. ATF2, activating transcription factor 2; CK, chemokine; DARC, Duffy antigen receptor for chemokines; EPO, erythropoietin; Gb3, globotriaosylceramide; GM‐CSF, granulocyte–macrophage colony‐stimulating factor; HMGI, high mobility group I; IFN‐γ, interferon‐γ; IL‐1, interleukin 1; IL‐1Ra, interleukin 1 receptor antagonist; IRF‐1, interferon regulatory factor 1; L, ligand; LPS, lipopolysaccharide; non‐γc, no common γ chain; PD, positive regulatory domain; PG, proteoglycans; R, receptor; VCAM‐1, vascular cellular adhesion molecule 1; VT, verotoxin. Modified from Mantovani et al. 1997 © Elsevier.
Figure 3. Functional programmes activated by cytokines in endothelial cells. Chemokines have both positive and negative effects on endothelial cells. Bold and plain types indicate the relative strengths of activation. EPO, erythropoietin; FGF, fibroblast growth factor; G‐CSF, granulocyte colony‐stimulating factor; GM‐CSF, granulocyte–macrophage colony‐stimulating factor; IFN‐γ, interferon‐γ; IL, interleukin; VEGF, vascular endothelium growth factor. Modified from Mantovani et al. 1997 © Elsevier.
Figure 4. The endothelium compartmentalises memory T‐cell response. The homing receptor expressed by memory T cells that preferentially migrate to the indicated organs are shown in the boxes.
Figure 5. Antigen‐dependent T‐cell trafficking. In cooperation with inflammatory signals such as chemokines (navy blue), by displaying tissue‐derived antigens (purple), endothelial cells promote the recruitment of specific activated T cells (orange) into the tissue.
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References

Alon R and van Buul JD (2017) Leukocyte breaching of endothelial barriers: the actin link. Trends in Immunology 38: 606–615.

Bazzoni G and Dejana E (2004) Endothelial cell‐to‐cell junctions: molecular organization and role in vascular homeostasis. Physiological Reviews 84: 869–901.

Burns AR, Walker DC, Brown ES, et al. (1997) Neutrophil transendothelial migration is independent of tight junctions and occurs preferentially at tricellular corners. Journal of Immunology 159: 2893–2903.

Busse R and Fleming I (2006) Vascular endothelium and blood flow. Handbook of Experimental Pharmacology 176: 43–78.

Butcher EC and Picker LJ (1996) Lymphocyte homing and homeostasis. Science 272: 60–66.

Butcher EC, Williams M, Youngman K, Rott L and Briskin M (1999) Lymphocyte trafficking and regional immunity. Advances in Immunology 72: 209–253.

Carman CV, Sage PT, Sciuto TE, et al. (2007) Transcellular diapedesis is initiated by invasive podosomes. Immunity 26: 784–797.

Carman CV (2009) Mechanisms for transcellular diapedesis: probing and pathfinding by ‘invadosome‐like protrusions’. Journal of Cell Science 122: 3025–3035.

Cheung K, Ma L, Wang G, et al. (2015) CD31 signals confer immune privilege to the vascular endothelium. Proceedings of the National Academy of Sciences of the United States of America 112: E5815–E5824.

Dejana E, Hirschi KK and Simons M (2017) The molecular basis of endothelial cell plasticity. Nature Communications 8: 14361.

Denk A, Goebeler M, Schmid S, et al. (2001) Activation of NF‐kappa B via the Ikappa B kinase complex is both essential and sufficient for proinflammatory gene expression in primary endothelial cells. Journal of Biological Chemistry 276: 28451–28458.

Fu H, Ward EJ and Marelli‐Berg FM (2016) Mechanisms of T cell organotropism. Cellular and Molecular Life Sciences 73: 3009–3033.

Gerard A, van der Kammen RA, Janssen H, Ellenbroek SI and Collard JG (2009) The Rac activator Tiam1 controls efficient T‐cell trafficking and route of transendothelial migration. Blood 113: 6138–6147.

Gonzalez‐Mariscal L, Tapia R and Chamorro D (2008) Crosstalk of tight junction components with signaling pathways. Biochimica et Biophysica Acta 1778: 729–756.

Granger DN and Kubes P (1994) The microcirculation and inflammation: modulation of leukocyte‐endothelial cell adhesion. Journal of Leukocyte Biology 55: 662–675.

Greening JE, Tree TI, Kotowicz KT, et al. (2003) Processing and presentation of the islet autoantigen GAD by vascular endothelial cells promotes transmigration of autoreactive T‐cells. Diabetes 52: 717–725.

Inohara N and Nunez G (2003) NODs: intracellular proteins involved in inflammation and apoptosis. Nature Reviews Immunology 3: 371–382.

Iwasaki A and Medzhitov R (2004) Toll‐like receptor control of the adaptive immune responses. Nature Immunology 5: 987–995.

Kempe S, Kestler H, Lasar A and Wirth T (2005) NF‐kappaB controls the global pro‐inflammatory response in endothelial cells: evidence for the regulation of a pro‐atherogenic program. Nucleic Acids Research 33: 5308–5319.

Lewis M, Tarlton JF and Cose S (2008) Memory versus naive T‐cell migration. Immunology and Cell Biology 86: 226–231.

Ley K and Kansas GS (2004) Selectins in T‐cell recruitment to non‐lymphoid tissues and sites of inflammation. Nature Reviews Immunology 4: 325–335.

Ley K and Reutershan J (2006) Leucocyte‐endothelial interactions in health and disease. Handbook of Experimental Pharmacology 176: 97–133.

Ley K, Laudanna C, Cybulsky MI and Nourshargh S (2007) Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Reviews Immunology 7: 678–689.

Manes TD and Pober JS (2008) Antigen presentation by human microvascular endothelial cells triggers ICAM‐1‐dependent transendothelial protrusion by, and fractalkine‐dependent transendothelial migration of, effector memory CD4+ T cells. Journal of Immunology 180: 8386–8392.

Mantovani A, Bussolino F and Dejana E (1992) Cytokine regulation of endothelial cell function. FASEB Journal 6: 2591–2599.

Mantovani A, Bussolino F and Introna M (1997) Cytokine regulation of endothelial cell function: from molecular level to the bedside. Immunology Today 18: 231–240.

Marelli‐Berg FM, Frasca L, Weng L, Lombardi G and Lechler RI (1999) Antigen recognition influences transendothelial migration of CD4+ T cells. Journal of Immunology 162: 696–703.

Marelli‐Berg FM, James MJ, Dangerfield J, et al. (2004) Cognate recognition of the endothelium induces HY‐specific CD8+ T‐lymphocyte transendothelial migration (diapedesis) in vivo. Blood 103: 3111–3116.

Marelli‐Berg FM, Clement M, Mauro C and Caligiuri G (2013) An immunologist's guide to CD31 function in T‐cells. Journal of Cell Science 126: 2343–2352.

Marmon S, Hinchey J, Oh P, et al. (2009) Caveolin‐1 expression determines the route of neutrophil extravasation through skin microvasculature. American Journal of Pathology 174: 684–692.

Mauge L, Terme M, Tartour E and Helley D (2014) Control of the adaptive immune response by tumor vasculature. Frontiers in Oncology 4: 61.

Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454: 428–435.

Mensah GA (2007) Healthy endothelium: the scientific basis for cardiovascular health promotion and chronic disease prevention. Vascular Pharmacology 46: 310–314.

Minshall RD and Malik AB (2006) Transport across the endothelium: regulation of endothelial permeability. Handbook of Experimental Pharmacology 176: 107–144.

Muller WA (2011) Mechanisms of leukocyte transendothelial migration. Annual Review of Pathology 6: 323–344.

Nourshargh S, Hordijk PL and Sixt M (2010) Breaching multiple barriers: leukocyte motility through venular walls and the interstitium. Nature Reviews Molecular Cell Biology 11: 366–378.

Nourshargh S and Alon R (2014) Leukocyte migration into inflamed tissues. Immunity 41: 694–707.

Oppenheimer‐Marks N and Lipsky PE (1996) Adhesion molecules as targets for the treatment of autoimmune diseases. Clinical Immunology and Immunopathology 79: 203–210.

Pantsulaia I, Ciszewski WM and Niewiarowska J (2016) Senescent endothelial cells: Potential modulators of immunosenescence and ageing. Ageing Research Reviews 29: 13–25.

Phillipson M, Heit B, Colarusso P, et al. (2006) Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. Journal of Experimental Medicine 203: 2569–2575.

Picker LJ and Butcher EC (1992) Physiological and molecular mechanisms of lymphocyte homing. Annual Review of Immunology 10: 561–591.

Pober JS and Cotran RS (1990) The role of endothelial cells in inflammation. Transplantation 50: 537–544.

Pober JS and Sessa WC (2007) Evolving functions of endothelial cells in inflammation. Nature Reviews Immunology 7: 803–815.

Savinov AY, Wong FS and Chervonsky AV (2001) IFN‐gamma affects homing of diabetogenic T cells. Journal of Immunology 167: 6637–6643.

Savinov AY, Wong FS, Stonebraker AC and Chervonsky AV (2003) Presentation of antigen by endothelial cells and chemoattraction are required for homing of insulin‐specific CD8+ T cells. Journal of Experimental Medicine 197: 643–656.

Schenkel AR, Mamdouh Z and Muller WA (2004) Locomotion of monocytes on endothelium is a critical step during extravasation. Nature Immunology 5: 393–400.

Sobel RA, Blanchette BW, Bhan AK and Colvin RB (1984) The immunopathology of experimental allergic encephalomyelitis. II. Endothelial cell Ia increases prior to inflammatory cell infiltration. Journal of Immunology 132: 2402–2407.

Taflin C, Charron D, Glotz D and Mooney N (2012) Regulation of the CD4+ T cell allo‐immune response by endothelial cells. Human Immunology 73: 1269–1274.

Walch JM, Zeng Q, Li Q, et al. (2013) Cognate antigen directs CD8+ T cell migration to vascularized transplants. Journal of Clinical Investigation 123: 2663–2671.

Wallez Y and Huber P (2008) Endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis. Biochimica et Biophysica Acta 1778: 794–809.

Wang S, Voisin MB, Larbi KY, et al. (2006) Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils. Journal of Experimental Medicine 203: 1519–1532.

Woodfin A, Voisin MB and Nourshargh S (2010) Recent developments and complexities in neutrophil transmigration. Current Opinion in Hematology 17: 9–17.

Further Reading

Alon R and Feigelson SW (2012) Chemokine‐triggered leukocyte arrest: force‐regulated bi‐directional integrin activation in quantal adhesive contacts. Current Opinion in Cell Biology 24: 670–676.

Capaldo CT and Nusrat A (2009) Cytokine regulation of tight junctions. Biochimica et Biophysica Acta 1788: 864–871.

Carman CV and Martinelli R (2015) T lymphocyte‐endothelial interactions: emerging understanding of trafficking and antigen‐specific immunity. Frontiers in Immunology 6: 603.

Cines DB, Pollak ES, Buck CA, et al. (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91: 3527–3561.

Garlanda C and Dejana E (1997) Heterogeneity of endothelial cells. Specific markers. Arteriosclerosis, Thrombosis, and Vascular Biology 17: 1193–1202.

Loftus JC and Liddington RC (1997) Cell adhesion in vascular biology. New insights into integrin‐ligand interaction. Journal of Clinical Investigation 99: 2302–2306.

Lucas R, Lou J, Morel DR, et al. (1997) TNF receptors in the microvascular pathology of acute respiratory distress syndrome and cerebral malaria. Journal of Leukocyte Biology 61: 551–558.

Luster AD, Alon R and von Andrian UH (2005) Immune cell migration in inflammation: present and future therapeutic targets. Nature Immunology 6: 1182–1190.

Mantovani A, Allavena P, Vecchi A and Sozzani S (1998) Chemokines and chemokine receptors during activation and deactivation of monocytes and dendritic cells and in amplification of Th1 versus Th2 responses. International Journal of Clinical and Laboratory Research 28: 77–82.

Marelli‐Berg FM, Clement M, Mauro C and Caligiuri G (2013) An immunologist's guide to CD31 function in T‐cells. Journal of Cell Science 126: 2343–2352.

Nourshargh S and Alon R (2014) Leukocyte migration into inflamed tissues. Immunity 41: 694–707.

Pober JS, Min W and Bradley JR (2009) Mechanisms of endothelial dysfunction, injury, and death. Annual Review of Pathology 4: 71–95.

Pober JS and Tellides G (2012) Participation of blood vessel cells in human adaptive immune responses. Trends in Immunology 33: 49–57.

Potente M and Carmeliet P (2017) The link between angiogenesis and endothelial metabolism. Annual Review of Physiology 79: 43–66.

Sperandio M, Gleissner CA and Ley K (2009) Glycosylation in immune cell trafficking. Immunological Reviews 230: 97–113.

Tang CY and Mauro C (2017) Similarities in the metabolic reprogramming of immune system and endothelium. Frontiers in Immunology 8: 837.

Zarbock A and Ley K (2009) Neutrophil adhesion and activation under flow. Microcirculation 16: 31–42.

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Cheung, Kenneth CP, Ward, Eleanor J, Fu, Hongmei, and Marelli‐Berg, Federica M(Jan 2018) Endothelial Cells: Immunological Aspects. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000513.pub3]