| 1. |
- Magnusson, Mattias, 1972, et al.
(författare)
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Requirement of type I interferon signaling for arthritis triggered by double-stranded RNA
- 2006
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Ingår i: Arthritis Rheum. - : Wiley. - 0004-3591 .- 1529-0131. ; 54:1, s. 148-57
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Arthralgias and overt arthritides are often associated with viral infections. Viral infections expose the infected host to proinflammatory double-stranded RNA (dsRNA), which can cause joint inflammation and is a potent activator of interferon-alpha (IFNalpha). The aim of this study was to determine the role of IFNalpha and dsRNA-related signaling molecules in the onset of joint inflammation induced by viral dsRNA. METHODS: IFNalpha and different forms of RNA were injected into the knee joints of wild-type mice, mice lacking the type I interferon receptor (IFNAR(-/-)), and mice deficient in dsRNA-dependent protein kinase (PKR(-/-)). Histologic evidence of joint damage and the ability of splenocytes to produce cytokines in response to dsRNA or IFNalpha were assessed. RESULTS: Viral dsRNA, but not short single-stranded RNA, induced arthritis. The arthritis was aggravated by intracellular delivery of dsRNA. The expression of PKR was not mandatory for dsRNA-induced joint inflammation. In contrast, IFNalpha/beta signaling was important for dsRNA-induced joint inflammation because IFNAR(-/-) mice did not develop arthritis. Furthermore, intraarticular deposition of IFNalpha induced arthritis in PKR(-/-) and control mice, whereas IFNAR(-/-) mice were protected. The arthritogenic effect of IFNalpha was attenuated by in vivo depletion of monocyte/macrophages. CONCLUSION: Arthritis triggered by dsRNA is not dependent on the expression of the dsRNA-signaling molecule PKR (or Toll-like receptor 3, as previously shown), but is associated with the ability to produce type I IFN and is critically dependent on type I IFN receptor signaling. The intrinsic arthritogenic properties of IFNalpha implicate a role of this cytokine in joint manifestations triggered by various interferogenic stimuli.
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| 2. |
- Zare, Fariba, 1972, et al.
(författare)
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Single-stranded polyinosinic acid oligonucleotides trigger leukocyte production of proteins belonging to fibrinolytic and coagulation cascades.
- 2008
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Ingår i: Journal of leukocyte biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 84:3, s. 741-7
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Tidskriftsartikel (refereegranskat)abstract
- The present study assessed the inductory effects of ds- and ssRNA on the leukocyte production of proteins belonging to fibrinolytic and coagulation cascades. Murine splenocytes were stimulated with dsRNA [polyinosinic:polycytidylic acid (polyIC)] and ssRNA sequences [polyinosinic acid (polyI), polycytidylic acid (polyC), and polyuridylic acid (polyU)]. The expression of plasminogen (Plg), tissue factor (TF), IL-6, and IFN-alpha was assessed. Intracellular transduction mechanisms activated by oligonucleotides were evaluated using specific inhibitors of signaling pathways and genetically modified mice. polyIC efficiently and dose-dependently induced the expression of Plg, IL-6, and IFN-alpha, whereas TF was not induced by polyIC. polyI was unable to trigger IFN-alpha production, and it was efficiently inducing Plg and TF. IFN-alphaR and dsRNA-dependent protein kinase signaling were not required for the polyI-induced production of Plg or TF. Neither polyU nor polyC induced the expression of Plg or TF. Importantly, the presence of U- and C-nucleotide strands in the dsRNA significantly reduced expression of Plg and TF compared with polyI alone. Exposure of splenocytes to polyI activated the NF-kappaB pathway followed by the expression of TF and IL-6. In contrast, Plg production did not require NF-kappaB, was only partly down-regulated by p38 MAPK inhibitor, and was efficiently inhibited by insulin, indicating a different mechanism for its induction. ssRNA exerts its TF-generating properties through NF-kappaB activation in an IFN-alpha-independent manner. The expression of fibrinolytic versus coagulation proteins is regulated through distinctly different transduction pathways. As fibrinolytic and coagulation cascades are important components of inflammatory homeostasis, these findings might have importance for development of new, targeted therapies.
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| 3. |
- Zare, Fariba, 1972, et al.
(författare)
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Uric acid, a nucleic acid degradation product, down-regulates dsRNA-triggered arthritis
- 2006
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Ingår i: J Leukoc Biol. - : Society for Leukocyte Biology. ; 79:3, s. 482-488
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Tidskriftsartikel (refereegranskat)abstract
- Uric acid, the naturally occurring degradation product of purine metabolism, is a danger signal, driving maturation of dendritic cells. It is well known that uric acid crystals display potent proinflammatory properties--the cause of gout--whereas the biological properties of soluble uric acid are less well documented. We have demonstrated previously that nucleic acids of endogenous and exogenous origin display proinflammatory properties. The aim of the present study was to assess the impact of soluble uric acid on in vivo inflammatory responses. Mice were administered with uric acid suspension in saline or saline alone prior to induction of neutrophil-mediated inflammation, delayed-type hypersensitivity, histamin-induced edema (measure of vasodilation capacity), as well as double-stranded (ds)RNA-triggered arthritis. Frequency and severity of arthritis were decreased significantly in mice exposed to dsRNA and simultaneously treated with uric acid as compared with saline-treated controls. Also, granulocyte-mediated inflammatory response and vasodilation capacity were reduced significantly in mice treated with uric acid as compared with their control group. The data suggest that down-regulation of inflammation was mediated by skewing the inflammatory response from the peripheral sites to the peritoneal cavity and down-regulating vasodilatatory capacity and thereby affecting leukocyte migration. In contrast, the T cell-mediated delayed-type hypersensitivity reaction was not affected significantly in mice exposed to uric acid. These findings demonstrate that uric acid displays a potent, distant anti-inflammatory effect in vivo. This property seems to be mediated by down-regulation of neutrophil influx to the site of inflammatory insult.
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| 4. |
- Nilton, Anna, et al.
(författare)
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Crooked, coiled and crimpled are three Ly6-like proteins required for proper localization of septate junction components.
- 2010
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Ingår i: Development (Cambridge, England). - : The Company of Biologists. - 1477-9129 .- 0950-1991. ; 137:14, s. 2427-37
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Tidskriftsartikel (refereegranskat)abstract
- Cellular junction formation is an elaborate process that is dependent on the regulated synthesis, assembly and membrane targeting of constituting components. Here, we report on three Drosophila Ly6-like proteins essential for septate junction (SJ) formation. SJs provide a paracellular diffusion barrier and appear molecularly and structurally similar to vertebrate paranodal septate junctions. We show that Crooked (Crok), a small GPI-anchored Ly6-like protein, is required for septa formation and barrier functions. In embryos that lack Crok, SJ components are produced but fail to accumulate at the plasma membrane. Crok is detected in intracellular puncta and acts tissue-autonomously, which suggests that it resides in intracellular vesicles to assist the cell surface localization of SJ components. In addition, we demonstrate that two related Ly6 proteins, Coiled (Cold) and Crimpled (Crim), are required for SJ formation and function in a tissue-autonomous manner, and that Cold also localizes to intracellular vesicles. Specifically, Crok and Cold are required for correct membrane trafficking of Neurexin IV, a central SJ component. The non-redundant requirement for Crok, Cold, Crim and Boudin (Bou; another Ly6 protein that was recently shown to be involved in SJ formation) suggests that members of this conserved family of proteins cooperate in the assembly of SJ components, possibly by promoting core SJ complex formation in intracellular compartments associated with membrane trafficking.
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| 5. |
- Zare, Fariba, 1972
(författare)
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Arthritogenecity of RNA and its degradation products
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Viral infections often lead to arthralgias and overt arthritic states. Expression of double stranded RNA (dsRNA) is a common feature of all viruses during their replication and it has been suggested that it is able to induce production of pro-inflammatory cytokines, e.g., interferon-alpha (IFN-alpha). The aims of this thesis were to investigate i) whether dsRNA induces arthritis, ii) the role of IFN-alpha regarding the onset of joint inflammation induced by viral dsRNA iii) the impact of dsRNA and single stranded RNA (ssRNA) on the production of proteins belonging to fibrinolytic and coagulation cascades and iiii) the impact of soluble uric acid on the in vivo inflammatory responses including development of dsRNA-triggered arthritis. Histological signs of arthritis were evident already on day three following intra-articular administration of dsRNA and IFN-a whereas ssRNA was not able to induce arthritis. Arthritis was characterized by infiltration of macrophages into synovial tissue. It was not dependent on acquired immune responses since SCID mice being deficient for T- and B-lymphocytes also developed arthritis. Although dsRNA is a ligand for TLR3 and intracellular PKR, TLR3KO and PKRKO mice developed arthritis indicating that some other receptors are instrumental in the induction of inflammation. Importantly, we found that dsRNA arthritis was triggered through IL-1R- and IFNalpha/beta-receptor-signalling since mice being deficient for these molecules were unable to raise joint inflammation. Furthermore, pro-inflammatory cytokines and chemokines including TNF-alpha, IFN-alpha, IL-6, MCP-1, MIP-1alpha and the transcription factor, NF-kappaB were readily triggered in response to stimulation of mouse splenocytes with dsRNA. In addition, we assessed the impact of RNA on coagulation and fibrinolytic cascades. DsRNA efficiently and dose-dependently induced the expression of plasminogen whereas tissue factor was induced only by certain ssRNA. It is well-known that uric acid crystals, the naturally occurring degradation product of purine metabolism, a danger signal driving maturation of dendritic cells, display potent pro-inflammatory properties, being the cause of gout. In contrast, the biological properties of soluble uric acid are less well documented. Frequency and severity of dsRNA-induced arthritis, granulocyte-mediated inflammatory response and vasodilatation capacity were significantly decreased in mice treated systemically with soluble uric acid as compared to the control group. The data suggest that uric acid displays potent distant anti-inflammatory effects in vivo. This property seems to be mediated by down-regulation of neutrophil influx to the site of inflammatory insult by localized chemotactic effect of uric acid. Collectively, these findings demonstrate that there is a link between joint inflammation and viral infection since viral dsRNA, by its capacity to induce production of IFN-alpha, is clearly arthritogenic. The end product of RNA, uric acid is able to maintain a balance in the body by modulation of the inflammatory responses.
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| 6. |
- Zare, Fariba, 1972, et al.
(författare)
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Arthritogenic properties of double-stranded (viral) RNA
- 2004
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Ingår i: J Immunol. - 0022-1767. ; 172:9, s. 5656-63
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Tidskriftsartikel (refereegranskat)abstract
- Viral infections often lead to arthralgias and overt arthritic states. The inflammatogenic compound of the viruses giving rise to such an outcome has to date not been identified. Because expression of dsRNA is a common feature of all viruses, we decided to analyze whether this property leads to the induction of arthritis. Histological signs of arthritis were evident already on day 3 following intra-articular administration of dsRNA. Arthritis was characterized by infiltration of macrophages into synovial tissue. It was not dependent on acquired immune responses because SCID mice also raised joint inflammation. NF-kappa B was activated upon in vitro exposure to dsRNA, indicating its role in the induction/progression of arthritis. Importantly, we found that dsRNA arthritis was triggered through IL-1R signaling because mice being deficient for this molecule were unable to develop joint inflammation. Although dsRNA is typically recognized by Toll-like receptor 3, Toll-like receptor 3 knockout mice developed arthritis, indicating that some other receptors are instrumental in the inducing of inflammation. Our results from in vitro experiments indicate that proinflammatory cytokines and chemokines stimulating monocyte influx were readily triggered in response to stimulation with dsRNA. These findings demonstrate that viral dsRNA is clearly arthritogenic. Importantly, macrophages and their products play an important role in the development of arthritis triggered by dsRNA.
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