Signaling mechanism of extracellular RNA in endothelial cells

Fischer, Silvia; Nishio, Miwako; Peters, Saskia C.; Tschernatsch, Marlene; Walberer, Maureen; Weidemann, Susanne; Heidenreich, Regina; Couraud, P. O.; Weksler, Babette B.; Romero, Ignacio A.; Gerriets, Tibo; Preissner, Klaus T.

doi:10.1096/fj.08-121608

Cited by 50 publications

(53 citation statements)

References 47 publications

(56 reference statements)

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“…We have demonstrated that serum from patients with ischemic stroke induces a powerful inflammatory response in cultured cells such as monocytes and endothelial cells. We analyzed several inflammatory markers that have been previously reported as markers for the activation of endothelial cells and monocytes (Damas et al, 2006;Fischer et al, 2009;Kamgang et al, 2008;Kikkert et al, 2008). As mentioned previously, treatment of cultured cells with serum from ischemic stroke patients induced an increase on the expression of inflammatory markers that was reduced when cells were pretreated with neutralizing antibodies against TLR2 and/or TLR4.…”

Section: Discussionmentioning

confidence: 96%

Toll-like receptors 2 and 4 in ischemic stroke: Outcome and therapeutic values

Brea

Blanco

Ramos‐Cabrer

et al. 2011

J Cereb Blood Flow Metab

151

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Stroke triggers an intense inflammatory response that could be a consequence of Toll-like receptors (TLRs) activation. However, the clinical significance and the therapeutic possibilities of TLR in stroke is not completely clear. In this study, we analyze the association between the expression of TLR2 and TLR4, inflammatory molecules and endogenous ligands, and clinical outcome of ischemic stroke patients, and we test the potential of TLR2/TLR4 and their endogenous ligands as therapeutic targets. For this purpose, we included 110 patients with ischemic stroke finding that TLR2 and TLR4 are independently associated to poor outcome and correlated with higher serum levels of interleukin (IL)1b, IL6, tumor necrosis factor a, and VCAM1, and that TLR4 was independently associated to lesion volume. In addition, we have developed an in vitro model to test the potential therapeutic value of blocking TLR2/TLR4 or their endogenous ligands. Cultured cells (monocytes and human umbilical vein endothelial cells) were treated with serum from ischemic stroke patients, showing a strong inflammatory response that was blocked when TLR2/4 or cellular fibronectin (cFN) or HSP60 were blocked. In conclusion, TLR2 and TLR4 are associated to outcome in stroke patients and TLR2/ 4 or their endogenous ligands, cFN/HSP60 could be new therapeutic targets for ischemic stroke.

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Section: Discussionmentioning

confidence: 96%

Toll-like receptors 2 and 4 in ischemic stroke: Outcome and therapeutic values

Brea

Blanco

Ramos‐Cabrer

et al. 2011

J Cereb Blood Flow Metab

151

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“…In previous studies, we showed that eRNA-induced vascular hyperpermeability or monocyte adhesion was promoted via the VEGF/VEGF-R2/neuropilin1 (NRP-1)-mediated signaling pathway (9,11). Accordingly, eRNA-induced tumor cell adhesion and transmigration were prevented by neutralizing antibodies against VEGF or the extracellular domain of NRP-1 ( Fig.…”

Section: Extracellular Rna-mediated Adhesion and Transmigration Of Tumentioning

confidence: 95%

“…TACE is a member of the A Disintegrin and Metalloprotease (ADAM) family and serves as sheddase to cleave the transmembrane form of tumor necrosis factor, thus generating the soluble form of active TNF-a (10). Permeability-increasing and proadhesive functions of eRNA are mediated by its interaction with VEGF leading to the activation of the VEGF-R2/neuropilin-1 (NRP-1) system (8,11). Collectively, eRNA serves as an endogenous alarm signal to provoke defense reactions that may expand into disease states.…”

Section: Introductionmentioning

confidence: 99%

Extracellular RNA Liberates Tumor Necrosis Factor-α to Promote Tumor Cell Trafficking and Progression

et al. 2013

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Extracellular RNA (eRNA) released from injured cells promotes tissue permeability, thrombosis, and inflammation in vitro and in vivo, and RNase1 pretreatment can reduce all these effects. In this study, we investigated the role of the eRNA/RNase1 system in tumor progression and metastasis. Under quiescent and stimulatory conditions, tumor cells released much higher levels of endogenous extracellular RNA (eRNA) than nontumor cells. In glioblastomas, eRNA was detected at higher levels in tumors than nontumor tissue. eRNA induced tumor cells to adhere to and migrate through human cerebral microvascular endothelial cells (HCMEC/D3), in a manner requiring activation of VEGF signaling. In addition, eRNA liberated TNF-a from macrophages in a manner requiring activation of the TNF-a-converting enzyme TACE. Accordingly, supernatants derived from eRNAtreated macrophages enhanced tumor cell adhesion to HCMEC/D3. TNF-a release evoked by eRNA relied upon signaling activation of mitogen-activated protein kinases and the NF-kB pathway. In subcutaneous xenograft models of human cancer, administration of RNase1 but not DNase decreased tumor volume and weight. Taken together, these results suggest that eRNA released from tumor cells has the capacity to promote tumor cell invasion through endothelial barriers by both direct and indirect mechanisms, including through a mechanism involving TNF-a release from tumor-infiltrating monocytes/macrophages. Our findings establish a crucial role for eRNA in driving tumor progression, and they suggest applications for extracellular RNase1 as an antiinvasive regimen for cancer treatment. Cancer Res; 73(16); 5080-9. Ó2013 AACR.

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“…It was previously shown that NRP-1 is highly expressed on RASF, and antiapoptotic signals of VEGF-A 165 were transduced by NRP-1 in RASF (52). Owing to binding of exRNA to VEGF, the interaction of RNA/VEGF complexes with VEGF-R2 and NRP-1 is increased, resulting in elevated vascular permeability (8). In RA and OA synovium, NRP-2, which is known to interact with VEGF and thus affects VEGF-induced signaling, was expressed in the lining layer.…”

Section: Effect Of Rnase On Rasf Cartilage Invasion In Vivomentioning

confidence: 99%

“…A s an endogenous alarm signal, eukaryotic extracellular RNA (exRNA) has been detected in the extracellular space of tissues, in plasma, cerebrospinal fluid, saliva, urine, and seminal fluid (1)(2)(3)(4)(5), and promotes immunoregulatory, procoagulatory, and vessel permeability-regulating functions (6)(7)(8)(9). Moreover, following cell activation, exRNA was found enriched in supernatants of human leukocytes, epithelial cells, cardiomyocytes, and various tumor cells (10)(11)(12)(13).…”

mentioning

confidence: 99%

Influence of Extracellular RNAs, Released by Rheumatoid Arthritis Synovial Fibroblasts, on Their Adhesive and Invasive Properties

Zimmermann-Geller

Köppert

Fischer

et al. 2016

The Journal of Immunology

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Extracellular RNA (exRNA) has been characterized as a molecular alarm signal upon cellular stress or tissue injury and to exert biological functions as a proinflammatory, prothrombotic, and vessel permeability–regulating factor. In this study, we investigated the contribution of exRNA and its antagonist RNase1 in a chronic inflammatory joint disease, rheumatoid arthritis (RA). Upon immunohistochemical inspection of RA, osteoarthritis (OA), and psoriatic arthritis synovium, exRNA was detectable only in the RA synovial lining layer, whereas extracellular DNA was detectable in various areas of synovial tissue. In vitro, exRNA (150–5000 nt) was released by RA synovial fibroblasts (RASF) under hypoxic conditions but not under normoxia or TNF-α treatment. RNase activity was increased in synovial fluid from RA and OA patients compared with psoriatic arthritis patients, whereas RNase activity of RASF and OASF cultures was not altered by hypoxia. Reduction of exRNA by RNase1 treatment decreased adhesion of RASF to cartilage, but it had no influence on their cell proliferation or adhesion to endothelial cells. In vivo, treatment with RNase1 reduced RASF invasion into coimplanted cartilage in the SCID mouse model of RA. We also analyzed the expression of neuropilins in synovial tissue and SF, as they may interact with vascular endothelial growth factor signaling and exRNA. The data support the concepts that the exRNA/RNase1 system participates in RA pathophysiology and that RASF are influenced by exRNA in a prodestructive manner.

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Signaling mechanism of extracellular RNA in endothelial cells

Cited by 50 publications

References 47 publications

Toll-like receptors 2 and 4 in ischemic stroke: Outcome and therapeutic values

Toll-like receptors 2 and 4 in ischemic stroke: Outcome and therapeutic values

Extracellular RNA Liberates Tumor Necrosis Factor-α to Promote Tumor Cell Trafficking and Progression

Influence of Extracellular RNAs, Released by Rheumatoid Arthritis Synovial Fibroblasts, on Their Adhesive and Invasive Properties

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