The endothelium is crucially important for the delivery of oxygen and nutrients throughout the body under homeostatic conditions. However, it also contributes to pathology, including the initiation and perpetuation of inflammation. Understanding the function of endothelial cells (ECs) in inflammatory diseases and molecular mechanisms involved may lead to novel approaches to dampen inflammation and restore homeostasis. In this article, we discuss the various functions of ECs in inflammation with a focus on pathological angiogenesis, attraction of immune cells, antigen presentation, immunoregulatory properties and endothelial-to-mesenchymal transition (EndMT). We also review the current literature on approaches to target these processes in ECs to modulate immune responses and advance anti-inflammatory therapies.
Career situation of first and presenting authorStudent for a master or a PhD.IntroductionTumour necrosis factor (TNF) is important in immune-mediated inflammatory diseases such as spondyloarthritis (SpA). Transmembrane (tm)TNF-transgenic (tg) mice1 that overexpress tmTNF develop SpA symptoms, including inflammation, ectopic lymphoid structures (ELS) in bone marrow (BM), bone destruction and bone formation. SpA patients have extensive angiogenesis in inflammatory and bone forming regions.ObjectivesTo investigate whether there is a link between pathological angiogenesis and ELS in tmTNF tg mice in the BM.MethodsAnkles, femora, tibiae, vertebrae and spleens from 6 and 12 weeks and 8 months old tmTNF tg mice and wild-type (WT) littermates (n=5 per age per group) were dissected and analyzed with confocal microscopy and analyzed 12 week old tmTNF tg and WT mice (n=4) with flow cytometry. To study the importance of TNF-R signaling, tmTNF tg mice lacking TNF-RI (tmTNF tgxTNF-RI-/-) or TNF-RII (tmTNF tgxTNF-RII-/-) (n=4 per group) were used.ResultsImmunofluorescent evaluation demonstrated that BM of tmTNF tg mice contained significantly more and extensive ELS. These ELS are limited to BM of the vertebrae and ankles, and are in close proximity of MECA79+high endothelial venules (HEVs). ELS predominantly consisted of B220+ B cells, of which most are IgD+ naive B cells. Preliminary flow cytometric analysis revealed a trend towards an increase in IgD-CD95+ germinal center B cells and CXCR5+PD-1+FoxP3-CTLA4- T follicular helper cells and CXCR5+PD-1+FoxP3+CTLA4+ in the vertebrae of tmTNF tg mice compared to WT littermates. Meanwhile, B cell lineages in the BM of tmTNF tg hind limbs were not altered. Furthermore, preliminary data indicates that BM and spleen from tmTNF tg mice contain more IgA+ plasma cells compared to WT littermates. tmTNF tgxTNF-RI-/- mice did not display lymphoid aggregates or HEVs in the BM, while tmTNF tgxTNF-RII-/- mice did, although to a lesser extent than tmTNF tg mice.ConclusionstmTNF overexpression in mice results in extensive ELS associated with HEVs in the BM, which is likely to be mediated through TNF-RI signaling. HEV formation may lead to persistence of inflammation in the BM which contributes to pathology.ReferenceAlexopoulou L, et al. Eur J Immunol 1997;27(10):2588–92Disclosure of InterestNone declared
IntroductionSpondyloarthritis is characterised by inflammation, extensive angiogenesis and pathological osteogenesis. Transmembrane (tm) TNF transgenic (tg) mice1 that overexpress tmTNF exhibit features of SpA, including chronic inflammation and pathological osteogenesis. tmTNF ligation to TNF receptor 2 in endothelial cells (ECs) can induce signal transduction pathways, that may promote these processes. Of note, angiogenesis and osteogenesis are coupled by EC differentiation towards a type H (CD31hiendomucinhi) phenotype.2 ObjectivesTo investigate the link between pathological angiogenesis and osteogenesis in tmTNF tg mice and the potential contribution of noncanonical NF-κB signalling in ECs to this process and infiltration of immune cells into the bone marrow (BM).MethodsVertebrae and ankles from 6 and 12 weeks and 8 months old tmTNF tg mice or sex-matched non-tg littermates (n=18) were prepared by cutting 60 µm thick cryosections for confocal imaging.ResultstmTNF tg mice exhibited ectopic osteogenesis which was not observed in non-tg littermates. Immunostainings showed that type H vessels are in the vicinity of the ectopic osteogenesis and osterix+ osteoprogenitors. At six weeks of age, osterix+ cells are located throughout the ectopic lesion, while at eight months, osterix+ cells are only present at the border of the lesion. Furthermore, there is increased osteogenesis and a different vessel architecture within the vertebrae of tmTNF tg mice compared to non-tg littermates that progresses with age. Non-tg littermate vertebrae only have physiological osteogenesis, which is in the metaphysis and periosteum. In addition, tmTNF tg mice also exhibit altered bone marrow (BM) architecture containing extensive lymphoid aggregates, which predominantly consisted of B220+ B cells.ConclusionstmTNF overexpression in mice leads to development of type H vessels associated with ectopic osteogenesis. In addition, extensive lymphoid aggregates develop in the BM. Current studies are aimed at identification of signalling pathways in ECs that contribute to these processes.References. Alexopoulou L, et al. Eur J Immunol1997;27(10):2588–92.. Kusumbe AP, et al. Nature2014;507(7492):323–328.Disclosure of interestNone declared
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