TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis

Meer, Jonathan H M van der; Poll, Tom van der; Veer, Cornelis van ’t

doi:10.1182/blood-2013-09-528752

Cited by 275 publications

(253 citation statements)

References 97 publications

(76 reference statements)

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“…Despite the high structural homology between GAS6 and PROS1, both ligands have distinct affinities to the TAM receptors and are also differentially expressed in various cell types (9). Furthermore, whereas the functions of GAS6 seem to be limited to those caused by activation of the TAM receptors, PROS1 has TAM receptor-dependent and independent activities (8,(10)(11)(12). In line with their discrete properties, GAS6 and PROS1 were shown to control distinct immune mechanisms in vitro and in vivo (7).…”

mentioning

confidence: 92%

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

Nassar

Tabib

Capucha

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critical for preventing local inflammation and the associated adverse systemic conditions. Nevertheless, the mechanisms by which the oral epithelium maintains homeostasis are poorly understood. Here, we studied the role of growth arrest specific 6 (GAS6), a ligand of the TYRO3–AXL–MERTK (TAM) receptor family, in regulating oral mucosal homeostasis. Expression of GAS6 was restricted to the outer layers of the oral epithelium. In contrast to protein S, the other TAM ligand, which was constitutively expressed postnatally, expression of GAS6 initiated only 3–4 wk after birth. Further analysis revealed that GAS6 expression was induced by the oral microbiota in a myeloid differentiation primary response gene 88 (MyD88)-dependent fashion. Mice lacking GAS6 presented higher levels of inflammatory cytokines, elevated frequencies of neutrophils, and up-regulated activity of enzymes, generating reactive nitrogen species. We also found an imbalance in Th17/Treg ratio known to control tissue homeostasis, as Gas6-deficient dendritic cells preferentially secreted IL-6 and induced Th17 cells. As a result of this immunological shift, a significant microbial dysbiosis was observed in Gas6−/− mice, because anaerobic bacteria largely expanded by using inflammatory byproducts for anaerobic respiration. Using chimeric mice, we found a critical role for GAS6 in epithelial cells in maintaining oral homeostasis, whereas its absence in hematopoietic cells synergized the level of dysbiosis. We thus propose GAS6 as a key immunological regulator of host–commensal interactions in the oral epithelium.

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mentioning

confidence: 92%

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

Nassar

Tabib

Capucha

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…hPS Attenuates Diabetes by Inhibiting Apoptosis hPS is a 69-kDa glycoprotein with anticoagulant, antiinflammatory, and antiapoptotic properties that is expressed by a variety of cells (8). It inhibits inflammation by decreasing leukocyte infiltration and the release of cytokines (e.g., interleukin-6, tumor necrosis factor-a [TNF-a]) and chemokines (MCP-1) by stimulating apoptotic cell clearance through macrophage-mediated phagocytosis or by blocking cell apoptosis through TAM receptors and the Akt/PKB pathway (9,(11)(12)(13).…”

Section: Discussionmentioning

confidence: 99%

“…PS may also directly stimulate the inhibition of the tissue factor pathway (7). In addition, PS regulates the inflammatory response and apoptosis pathways through Tyro3, Axl, and Mer (TAM) tyrosine kinase receptors (8). PS inhibits the expression of inflammatory cytokines from a variety of cells and is protective against lipopolysaccharide-induced acute lung injury (9).…”

mentioning

confidence: 99%

Amelioration of Diabetes by Protein S

et al. 2016

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Protein S is an anticoagulant factor that also regulates inflammation and cell apoptosis. The effect of protein S on diabetes and its complications is unknown. This study compared the development of diabetes between wildtype and transgenic mice overexpressing human protein S and the development of diabetic glomerulosclerosis between mice treated with and without human protein S and between wild-type and protein S transgenic mice. Mice overexpressing protein S showed significant improvements in blood glucose level, glucose tolerance, insulin sensitivity, and insulin secretion compared with wild-type counterparts. Exogenous protein S improved insulin sensitivity in adipocytes, skeletal muscle, and liver cell lines in db/db mice compared with controls. Significant inhibition of apoptosis with increased expression of BIRC3 and Bcl-2 and enhanced activation of Akt/PKB was induced by protein S in islet b-cells compared with controls. Diabetic wild-type mice treated with protein S and diabetic protein S transgenic mice developed significantly less severe diabetic glomerulosclerosis than controls. Patients with type 2 diabetes had significantly lower circulating free protein S than healthy control subjects. This study shows that protein S attenuates diabetes by inhibiting apoptosis of b-cells and the development of diabetic nephropathy.

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“…Para diferenciar entre ambos mecanismos, en el primero se aprecia una trombocitopenia moderada acompañada también de una disminución de leucocitos por secuestro esplénico (30,31). Al respecto existen 2 grandes series que señalan a la esplenectomía (abordaje tradicional o laparoscópico) como medida terapéutica que ayuda a elevar las cifras de plaquetas (>100 x10 el hecho de que existen homólogos de la proteína S en algunos tumores hepáticos (59,60).…”

Section: Factor De Von Willebrand (Fvw)unclassified

Insuficiencia hepática crónica y hemostasia

Peñafiel

Sánchez

et al. 2017

Rev. Colomb. Gastroenterol.

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ResumenLa insuficiencia hepática es un estado patológico que condiciona la síntesis y metabolismo de diversas biomoléculas, siendo las alteraciones a la hemostasia una de las primeras consecuencias a nivel sistémico que se hacen presentes; debido a esto y por la dimensión de los riesgos de esta situación, no es raro que las pruebas de coagulación sean indispensables para formular las escalas pronósticas en pacientes hepatópatas.Los conocimientos sobre hemostasia han avanzado en la última década; la clásica cascada de activación de los factores de la coagulación ha sido perfeccionada hasta conformarse el ahora vigente modelo celular que considera la valiosa e indispensable participación del endotelio y las plaquetas. Gracias a esto es posible comprender que, en pacientes con insuficiencia hepática, el riesgo de sangrado no obedece únicamente a la deficiencia en la producción de los factores de la coagulación y, por tanto, es cuestionable la administración de vitamina K. Más relevante aún es que, gracias a estos conocimientos, se puede comprender el a veces contradictorio riesgo de trombosis en estos pacientes, complicación potencialmente mortal. Palabras claveCoagulación sanguínea, insuficiencia hepática, trombosis, vitamina K. AbstractHepatic insufficiency is a pathology that conditions synthesis and metabolism of various biomolecules. Alterations of hemostasis is one of its first systemic consequences. Because of this and the size of the risks, it is not uncommon for clotting tests to be indispensable for formulating prognostic scales in patients with liver disease.Knowledge about hemostasis has advanced in the last decade, and the classic cascade of activation of coagulation factors has been perfected until it has become the now-current cellular model that considers the valuable and indispensable participation of the endothelium and platelets. Thanks to this, it is possible to understand that the risk of bleeding in patients who have hepatic insufficiency is not only due to deficiencies in production of coagulation factors, and that for this reason administration of vitamin K is questionable. Even more relevant, is the fact that, thanks to this this knowledge, we can understand the sometimes contradictory and potentially life-threatening complication of thrombosis in these patients.

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TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis

Cited by 275 publications

References 97 publications

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

GAS6 is a key homeostatic immunological regulator of host–commensal interactions in the oral mucosa

Amelioration of Diabetes by Protein S

Insuficiencia hepática crónica y hemostasia

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