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- Ali, Abukar, 1988, et al.
(författare)
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Antibiotic-killed Staphylococcus aureus induces destructive arthritis in mice.
- 2015
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Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - : Wiley. - 2326-5205 .- 2326-5191. ; 67:1, s. 107-116
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Permanent reduction in joint function is a severe post-infectious complication in patients with Staphylococcus aureus septic arthritis. This reduction in joint function might be caused by persistent joint inflammation after the adequate eradication of bacteria by antibiotics. Methods: We studied whether antibiotic-killed S. aureus induced joint inflammation in mice and elucidated the molecular and cellular mechanism of this type of arthritis. Results: The intraarticular injection of antibiotic-killed S. aureus induced mild to moderate synovitis and bone erosions that lasted for a minimum of 14 days. The frequency and severity of synovitis were significantly reduced in tumor necrosis factor receptor 1 (TNFR1), receptor for Advanced Glycation End Products (RAGE), and toll like receptor 2 (TLR2) knockout mice compared with wild-type animals. The combined depletion of monocytes and neutrophils resulted in a significantly lower frequency of synovitis. Among bacterial factors, insoluble cell debris played a more important role than bacterial DNA or soluble components in inducing joint inflammation. Importantly, anti-TNF therapy abrogated the joint inflammation induced by antibiotic-killed S. aureus. Conclusion: Antibiotic-killed S. aureus induced and maintained the joint inflammation that is mediated through TLR2, TNFR1, and RAGE receptor. The cross-talk between neutrophils and monocytes is responsible for this type of arthritis. Anti-TNF therapy might be used as a novel therapeutic strategy, in combination with antibiotics, to treat staphylococcal septic arthritis. © 2014 American College of Rheumatology.
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- ALi, Kassem, et al.
(författare)
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Toll-like receptor induced inflammation causes local bone formation
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- It is well established that inflammatory processes in the vicinity of bone often induce osteoclast formation and bone resorption. Effects on bone formation by inflammatory processes are much less studied and available information is partly contradictory. In the present study, we have assessed the effect on bone formation by locally induced inflammation. LPS from Porphyromonas gingivalis and Pam2, used as Toll-like receptor (TLR) 2 agonists, and flagellin from Salmonella typhimurium, used as TLR5 agonist, were injected subcutaneously on the top of mouse skull bones. After 1-5 days, the calvarial bones were dissected and processed either for histological or gene expression analyses. Femur was dissected for analysis with microCT and histology. At day 5, all three agonists induced bone formation on periosteal and endosteal sites, as well as in the bone marrow compartment of the calvaria. This response was seen both in close vicinity to, but also apart from, osteoclasts and bone resorption cavities. In areas close to new bone formation, abundance of proliferating cells was observed as assessed by Ki67 labelling. Gene expression analyses showed that Pam2 treatment resulted in increased mRNA expression at day 5 of genes encoding bone matrix proteins, alkaline phosphatase and of the osteoblastic transcription factors Runx2 and osterix. Robust Runx2 protein was observed in osteoblasts in areas with new bone formation. Pam2 treatment also increased the mRNA expression of cytokines in the IL-6 family, as well as of their cognate receptors and common signaling transduction subunit gp130. At day 5, the mRNA expression of Bmp2, Bmp4, Tgfb1, Lrp5, Lrp6 and Wnt7b was increased, whereas Sost was decreased. In the femur, excessive osteoclast formation and trabecular bone loss was found at day 5, but new bone formation was not observed. In conclusion, these data show that inflammatory processes not only induce osteoclastogenesis but also have the capacity to activate osteoblasts and stimulate new bone formation distinct from bone remodeling sites. Stimulation of inflammation- induced new bone formation may be due to enhanced gp130 signaling. Osteoblast activation in the inflammatory processes may also involve the BMP and WNT signaling systems.
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- Andersson, Niklas, 1970, et al.
(författare)
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Investigation of central versus peripheral effects of estradiol in ovariectomized mice
- 2005
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Ingår i: J Endocrinol. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 187:2, s. 303-9
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Tidskriftsartikel (refereegranskat)abstract
- It is generally believed that estrogens exert their bone sparing effects directly on the cells within the bone compartment. The aim of the present study was to investigate if central mechanisms might be involved in the bone sparing effect of estrogens. The dose-response of central (i.c.v) 17beta-estradiol (E2) administration was compared with that of peripheral (s.c.) administration in ovariectomized (ovx) mice. The dose-response curves for central and peripheral E2 administration did not differ for any of the studied estrogen-responsive tissues, indicating that these effects were mainly peripheral. In addition, ovx mice were treated with E2 and/or the peripheral estrogen receptor antagonist ICI 182,780. ICI 182,780 attenuated most of the estrogenic response regarding uterus weight, retroperitoneal fat weight, cortical BMC and trabecular bone mineral content (P<0.05). These findings support the notion that the primary target tissue that mediates the effect of E2 on bone is peripheral and not central.
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- Bergmann, Berglind, et al.
(författare)
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Antibiotics with Interleukin-15 inhibition reduces joint inflammation and bone erosions but not cartilage destruction in Staphylococcus aureus-induced arthritis.
- 2018
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Ingår i: Infection and immunity. - 1098-5522. ; 86:5
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Tidskriftsartikel (refereegranskat)abstract
- Background:Staphylococcus aureus-induced arthritis causes rapid joint destruction, often leading to disabling joint damage despite antibiotics. We have previously shown that IL-15 inhibition without antibiotics is beneficial in S. aureus-induced arthritis. We therefore hypothesized that inhibition of IL-15, in combination with antibiotics, might represent a useful therapy that would both reduce inflammation and joint destruction, but preserve the host's ability to clear the infection.Methods: Female wildtype C57BL/6 mice were intravenously inoculated with the TSST-1-producing LS-1 strain of S. aureus with 0.8x108S. aureus LS-1/mouse. Three days later the treatment was started consisting of cloxacillin followed by flucloxacillin, together with either anti-IL-15 antibodies (aIL-15ab) or control antibodies. Outcomes included survival, weight change, bacterial clearance, and joint damage.Results: The addition of aIL-15ab to antibiotics in S. aureus-induced arthritis reduced synovitis and bone erosions compared to controls. The number of bone-resorbing osteoclasts in the joints was reduced, whereas cartilage destruction was not significantly altered. Importantly, the combination therapy did not adversely affect the clinical outcome of S. aureus-induced arthritis, such as survival, weight change or compromise the host's ability to clear the infection.Conclusions: As the clinical outcome of S. aureus-induced arthritis was not affected, the addition of aIL-15ab to antibiotics ought to be safe. Taken together, the combination of aIL-15ab and antibiotics is a beneficial, but not optimal, treatment of S. aureus-induced arthritis as it reduces synovitis and bone erosions but has a limited effect on cartilage destruction.
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- Bergmann, Berglind, et al.
(författare)
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Pre-treatment with IL2 gene therapy alleviates Staphylococcus aureus arthritis in mice.
- 2020
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Ingår i: BMC infectious diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis.C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage.Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host's ability to clear the infection.Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.
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- Bergquist, Maria, et al.
(författare)
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Expression of the glucocorticoid receptor is decreased in experimental Staphylococcus aureus sepsis
- 2013
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Ingår i: Journal of Infection. - : Elsevier BV. - 0163-4453 .- 1532-2742. ; 67:6, s. 574-583
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Glucocorticoid treatment in septic shock remains controversial after recent trials. We hypothesized that failure to respond to steroid therapy may be caused by decreased expression and/or function of glucocorticoid receptors (GR) and studied this in a mouse model of Staphylococcus aureus sepsis. The impact of timing of dexamethasone treatment was also investigated. Methods: Male C57BL/6J mice were intravenously inoculated with S. aureus and GR expression and binding ability in blood, spleen and lymph nodes were analysed by means of flow cytometry. GR translocation was analysed using Image Stream. Septic mice were administered dexamethasone at 22, 26, 48, 72 and 96 h after inoculation and body weight, as a sign of dehydration, was observed. Results: GR expression was decreased in septic animals, but not the ligand binding capacity. GR translocation was decreased in septic mice compared to control animals. Early dexamethasone treatment (22 and 26 h) improved clinical outcome as studied by weight gain compared to when treatment was started at later time points (48, 72 and 96 h). Conclusion: Our data provide evidence that GR expression is progressively decreased in experimental sepsis and that dexamethasone has a decreased ability to translocate into the cell nucleus. This may explain why steroid treatment is only beneficial when administered early in sepsis and septic shock.
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