| 1. |
- Agalave, Nilesh M., et al.
(författare)
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Sex-dependent role of microglia in disulfide high mobility group box 1 protein-mediated mechanical hypersensitivity
- 2021
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Ingår i: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 162:2, s. 446-458
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Tidskriftsartikel (refereegranskat)abstract
- High mobility group box 1 protein (HMGB1) is increasingly regarded as an important player in the spinal regulation of chronic pain. Although it has been reported that HMGB1 induces spinal glial activation in a Toll-like receptor (TLR)4-dependent fashion, the aspect of sexual dimorphisms has not been thoroughly addressed. Here, we examined whether the action of TLR4-activating, partially reduced disulfide HMGB1 on microglia induces nociceptive behaviors in a sex-dependent manner. We found disulfide HMGB1 to equally increase microglial Iba1 immunoreactivity in lumbar spinal dorsal horn in male and female mice, but evoke higher cytokine and chemokine expression in primary microglial culture derived from males compared to females. Interestingly, TLR4 ablation in myeloid-derived cells, which include microglia, only protected male mice from developing HMGB1-induced mechanical hypersensitivity. Spinal administration of the glial inhibitor, minocycline, with disulfide HMGB1 also prevented pain-like behavior in male mice. To further explore sex difference, we examined the global spinal protein expression using liquid chromatography-mass spectrometry and found several antinociceptive and anti-inflammatory proteins to be upregulated in only male mice subjected to minocycline. One of the proteins elevated, alpha-1-antitrypsin, partially protected males but not females from developing HMGB1-induced pain. Targeting downstream proteins of alpha-1-antitrypsin failed to produce robust sex differences in pain-like behavior, suggesting that several proteins identified by liquid chromatography-mass spectrometry are required to modulate the effects. Taken together, the current study highlights the importance of mapping sex dimorphisms in pain mechanisms and point to processes potentially involved in the spinal antinociceptive effect of microglial inhibition in male mice.
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| 2. |
- Ahmed, Aisha Siddiqah, et al.
(författare)
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Proteasome inhibitor MG132 modulates inflammatory pain by central mechanisms in adjuvant arthritis.
- 2017
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Ingår i: International journal of rheumatic diseases. - 1756-185X. ; 20:1, s. 25-32
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: In rheumatoid arthritis (RA), pain and inflammation are initial symptoms followed by various degrees of bone and cartilage destruction. Previously, we have shown that reversible proteasome inhibitor MG132 attenuates pain and joint inflammation in a rat model of adjuvant-arthritis. Our present study aims to study the effects of MG132 on molecular changes in the dorsal root ganglia (DRG) and in the spinal cord (SC) using the same animal model.METHODS: Arthritis was induced by heat-killed Mycobacterium butyricum in rats. The expression of substance P (SP) was analyzed by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in DRG and in the SC. The nuclear factor-κB (NF-κB) DNA-binding activity in the SC was analyzed by electromobility shift assay.RESULTS: Arthritic rats treated daily with MG132 demonstrated a marked reduction of SP gene expression in the DRG and number of SP-positive cells was reduced. In the spinal cord of arthritic rats elevated SP messenger RNA levels were normalized and NF-κB-DNA-binding activity was down-regulated in arthritic rats treated with MG132.CONCLUSION: Our results indicate that proteasome inhibitor MG132 attenuates pain in adjuvant arthritis by targeting the sensory neuropeptide substance P in the peripheral and central nervous systems. These effects may be mediated through the inhibition of NF-κB activation.
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| 3. |
- Ahmed, Aisha S, et al.
(författare)
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Suppression of pain and joint destruction by inhibition of the proteasome system in experimental osteoarthritis
- 2012
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 153:1, s. 18-26
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Tidskriftsartikel (refereegranskat)abstract
- Osteoarthritis is a degenerative joint disease with pain and loss of joint function as major pathological features. Recent studies show that proteasome inhibitors reduce pain in various pathological conditions. We evaluated the effects of MG132, a reversible proteasome inhibitor on pain and joint destruction in a rat model of osteoarthritis. Osteoarthritis was induced by intraarticular injection of monosodium iodoacetate into the rat knee. Knee joint stiffness was scored and nociception was evaluated by mechanical pressure applied to the respective hind paw. Knee joint destruction was assessed by radiological and histological analyses. Expression of matrix metalloproteinase-3 (MMP-3) was analyzed by quantitative reverse transcription polymerase chain reaction in the knee articular cartilage. Expression of substance P (SP) and calcitonin gene-related peptide (CGRP) was studied in the dorsal root ganglia (L4–L6) by quantitative reverse transcription polymerase chain reaction and in the knee joints by immunohistochemistry. Our results indicate that daily treatment of osteoarthritic rats with MG132 significantly increases their mobility while the swelling, pain thresholds, and pathological features of the affected joints were reduced. Furthermore, the upregulated expression of MMP-3, SP, and CGRP in the arthritic rats was normalized by MG132 administration. We conclude that the proteasome inhibitor MG132 reduces pain and joint destruction, probably by involving the peripheral nervous system, and that changes in SP and CGRP expression correlate with alterations in behavioural responses. Our findings suggest that nontoxic proteasome inhibitors may represent a novel pharmacotherapy for osteoarthritis.
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| 4. |
- Erlandsson Harris, Helena
(författare)
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Studies of the immunopathogenesis in three arthritis models in rats
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The immunopathogenesis of three arthritis models has been studied; oil-induced arthritis (OIA), homologous collagen-induced arthritis (CIA) and COMP-induced arthritis. The induction of a monophasic arthritis, OIA, in the DA rat with a single intradermal injection of Freund's incomplete adjuvant (FIA) was reported. The involvement of specific immunity in the disease course was implicated by the failure to reinduce the disease in animals that had once recovered from OIA. No humoral or cellular responses to screened cartilage antigens could be detected. The potency of FIA in inducing arthritis was demonstrated by the induction of arthritis via percutaneous exposure to FIA. Repeated treatments with FIA on lightly abrased skin was the most effective means of inducing OIA. The involvement of T-cells in the disease was confirmed by the transfer of passive OIA with CD4+ T-cells from rats with active OIA. These findings highlight the role of adjuvants in inducing experimental autoimmune diseases, and indicate the importance of studying adjuvants in the context of human autoimmune diseases. Analysis of the T-cell receptor (TcR) VB gene usage, by PCR, of T-cells infiltrating the SMs in rats with CIA demonstrated a restricted usage early in disease whereas at a later timepoint no restriction was evident. At no timepoint could such a restriction be detected in the draining Iymphnodes. These results raise the possibility that similar TcR VB may indeed be used by arthritis-associated T-cells in two different species, and it also demonstrates the importance of studying early disease timepoints when analyzing TcR VB expression. Histological characterization, by immunohistochemistry, of the cellular infiltrates in synovial fluid (SF) and synovial membranes (SM) in CIA revealed a different cellular picture in SF as compared to SM. The SF was dominated by polymorphonuclear cells while SM mainly consisted of mononuclear cells. Investigation of adhesion molecules expressed in these compartments suggests that expression of CD49d and CD49f in SM might retain mononuclear cells while polymorphonuclear cells migrate to the SF, possibly due to attraction by immune complexes. These results indicate different mechanisms behind the inflammation in SF compared to the inflammation in SM. Analysis of antibody (ab) reactivities to CII, hsp 65kD and the presence of rheumatoid factors (RF) revealed equally high levels of investigated ab in both SF and in sera. Interestingly, normal rats of the autoimmune-prone DA strain had high levels of RF, higher than those in the arthritis-resistant F344 rat strain. Finally, the induction of arthritis with the cartilage protein COMP was reported. Bovine COMP mixed with FIA induced a monophasic arthritis in Lew1av1 rats. Cellular and humoral responses to COMP were detected, as was a strong production of TNF-a and IL-2 by Iymphnode cells. No cross-reactivity to CII could be detected.
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| 5. |
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| 6. |
- Lundbäck, Peter, et al.
(författare)
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A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice
- 2016
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Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 64:5, s. 1699-1710
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Tidskriftsartikel (refereegranskat)abstract
- Acetaminophen (APAP) overdoses are of major clinical concern. Growing evidence underlines a pathogenic contribution of sterile postinjury inflammation in APAP-induced acute liver injury (APAP-ALI) and justifies development of anti-inflammatory therapies with therapeutic efficacy beyond the therapeutic window of the only current treatment option, N-acetylcysteine (NAC). The inflammatory mediator, high mobility group box 1 (HMGB1), is a key regulator of a range of liver injury conditions and is elevated in clinical and preclinical APAP-ALI. The anti-HMGB1 antibody (m2G7) is therapeutically beneficial in multiple inflammatory conditions, and anti-HMGB1 polyclonal antibody treatment improves survival in a model of APAP-ALI. Herein, we developed and investigated the therapeutic efficacy of a partly humanized anti-HMGB1 monoclonal antibody (mAb; h2G7) and identified its mechanism of action in preclinical APAP-ALI. The mouse anti-HMGB1 mAb (m2G7) was partly humanized (h2G7) by merging variable domains of m2G7 with human antibody-Fc backbones. Effector function-deficient variants of h2G7 were assessed in comparison with h2G7 in vitro and in preclinical APAP-ALI. h2G7 retained identical antigen specificity and comparable affinity as m2G7. 2G7 treatments significantly attenuated APAP-induced serum elevations of alanine aminotransferase and microRNA-122 and completely abrogated markers of APAP-induced inflammation (tumor necrosis factor, monocyte chemoattractant protein 1, and chemokine [C-X-C motif] ligand 1) with prolonged therapeutic efficacy as compared to NAC. Removal of complement and/or Fc receptor binding did not affect h2G7 efficacy. Conclusion: This is the first report describing the generation of a partly humanized HMGB1-neutralizing antibody with validated therapeutic efficacy and with a prolonged therapeutic window, as compared to NAC, in APAP-ALI. The therapeutic effect was mediated by HMGB1 neutralization and attenuation of postinjury inflammation. These results represent important progress toward clinical implementation of HMGB1-specific therapy as a means to treat APAP-ALI and other inflammatory conditions. (Hepatology 2016;64:1699-1710).
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| 7. |
- Pullerits, Rille, 1969, et al.
(författare)
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High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis.
- 2003
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Ingår i: Arthritis and Rheumatism. - 1529-0131. ; 48:6, s. 1693-1700
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the potential role of high mobility group box chromosomal protein 1 (HMGB-1) in the pathogenesis of arthritis. METHODS: Mice were injected intraarticularly with 1 microg or 5 microg of HMGB-1. Joints were dissected on days 4, 7, and 28 after injection and were evaluated histopathologically and immunohistochemically. To investigate the importance of different white blood cell populations for the development of arthritis, in vivo cell depletion procedures were performed. In addition, spleen cells were cultured in the presence of HMGB-1, and nuclear factor kappaB (NF-kappaB) activation was detected by electrophoretic mobility shift assay. RESULTS: Injection of recombinant HMGB-1 (rHMGB-1) into different mouse strains resulted in an overall frequency of arthritis in 80% of the animals. The inflammation was characterized by mild to moderate synovitis and lasted for at least 28 days. The majority of cells found in the inflamed synovium were Mac-1+ macrophages, whereas only a few CD4+ lymphocytes were detected. Pannus formation was observed in some cases 7 and 28 days after HMGB-1 injection. No significant differences were found with respect to incidence and severity of arthritis between mice depleted of monocytes, granulocytes, or lacking T/B lymphocytes. However, combined removal of monocytes and neutrophils resulted in a 43% lower incidence of arthritis. Mice rendered deficient in the interleukin-1 (IL-1) receptor did not develop inflammation upon challenge with HMGB-1. In vitro data corroborate this finding, showing that rHMGB-1 activated NF-kappaB, a major pathway leading to IL-1 production. CONCLUSION: Our results indicate that HMGB-1 is not a mere expression of inflammatory responses, but on its own, it triggers joint inflammation by activating macrophages and inducing production of IL-1 via NF-kappaB activation.
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| 8. |
- Schierbeck, Hanna, et al.
(författare)
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Evaluation of the danger signal HMGB1 as a potential biomarker in juvenile idiopathic arthritis (JIA): a preliminary study using the novel biobank jabba
- 2012
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Ingår i: Ann Rheum Dis 2012. ; 71:Suppl 1
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Konferensbidrag (refereegranskat)abstract
- Background and objectives: The endogenous danger signal High Mobility Group Box protein 1 (HMGB1) promotes inflammation. HMGB1 has been implicated as a mediator of RA while there are no reports describing its presence in JIA patient samples. HMGB1 is aberrantly expressed in the synovitis of RA patients, intraarticular injection of HMGB1 induces arthritis in mice and HMGB1 blockade has beneficial effects in several different experimental disease models, including arthritis. In this study, the aim was to determine whether HMGB1 is extracellularly increased during JIA and, if so, to correlate the HMGB1 levels both with other more well-described laboratory parameters and with clinical parameters such as age at onset and disease duration. This type of descriptive study forms the basis for the evaluation of HMGB1 as a biomarker of inflammatory activity during JIA and as a potential therapeutic target. The newly established JIA biobank JABBA coupled to a clinical register gives us a unique opportunity to study JIA pathogenesis. Materials and methods: Plasma and synovial fluid (SF) was collected from 23 patients with JIA (median age 12 (2–18)) at Astrid Lindgren Children's hospital, Stockholm, Sweden and at Tartu University Children's Hospital, Estonia. Samples were analysed by ELISA and Cytometric bead array (CBA) to measure levels of HMGB1, MMP-3, sRAGE, IL-12p70, TNF, IL-10, IL-6, IL-1β, IL-8, MCP-1, IP-10, RANTES, IFNγ, IFNα and IL-17A. Results: Increased HMGB1 levels were recorded in SF as compared to plasma from JIA patients. Highest levels of HMGB1 were recorded in patients with a disease onset in early age (before age 10), while no correlation between the HMGB1 levels and disease duration was evident. In contrast, both S100 and IL-8 levels correlated with disease duration being highest during early stages of disease. MMP-3, a marker of cartilage destruction, was higher in patients with late disease onset which indicates similarities with RA. Conclusion: The increased levels of HMGB1 in inflamed joints of JIA patients warrants further studies of HMGB1 as a biomarker for inflammatory activity and as a target for therapy. The correlation of HMGB1 levels with age at disease onset and continuously high levels irrespective of disease duration indicates, together with the decreasing levels of S100 and IL-8 during the disease course, that the inflammatory process in JIA evolves over time. Different mediators might thus be of varying importance during the disease progression. The authors conclude that the role of HMGB1 in the pathogenesis of JIA deserves further investigation.
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| 9. |
- Schierbeck, Hanna, et al.
(författare)
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HMGB1 Levels Are Increased in Patients with Juvenile Idiopathic Arthritis, Correlate with Early Onset of Disease, and Are Independent of Disease Duration.
- 2013
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Ingår i: The Journal of rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 40:9, s. 1604-1613
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Tidskriftsartikel (refereegranskat)abstract
- High mobility group box chromosomal protein 1 (HMGB1) has been implicated as a mediator of inflammation in rheumatoid arthritis (RA), while its role in juvenile idiopathic arthritis (JIA) has not been described. To evaluate the role of HMGB1 in the inflammatory process in JIA and its potential as a therapeutic target, we investigated whether extracellular HMGB1 is detectable in JIA and if so, to correlate the levels with established inflammatory markers and clinical measures.
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| 10. |
- Struglics, André, et al.
(författare)
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Juvenile idiopathic arthritis patients have a distinct cartilage and bone biomarker profile that differs from healthy and knee-injured children
- 2020
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Ingår i: Clinical and Experimental Rheumatology. - : Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 38:2, s. 355-365
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Joint destruction is a hallmark of juvenile idiopathic arthritis (JIA). Clinical evaluation and radiographic imaging are current methods to identify destruction. Biomarkers could aid an earlier and more sensitive diagnosis. Our aim was to investigate levels of bone and cartilage degradation biomarkers in JIA patients, compared to healthy children or juveniles with knee injuries. METHODS: Triple-paired synovial fluid, plasma and urine samples from 29 JIA patients were compared to 61 plasma samples from healthy children and synovial fluid from 41 knee-injured juveniles. Cartilage biomarkers ARGS neoepitope of aggrecan (ARGS), cartilage oligomeric matrix protein (COMP), type II collagen epitope (C2C), bone biomarkers N-terminal type I collagen cross-linked telopeptide (NTX-I) and tartrate-resistant acid phosphatase 5b (TRAP5b) were analysed by immunoassays. RESULTS: Plasma levels of ARGS, C2C, COMP and TRAP5b were increased in JIA compared to healthy children. Compared to knee-injured juveniles, synovial fluid C2C and TRAP5b were increased in JIA, while ARGS and COMP were decreased. For JIA patients, local (synovial fluid) and systemic (plasma/urine) levels of bone biomarkers correlated positively; age correlated negatively to plasma levels of C2C and TRAP5b; no correlation was found between biomarkers and gender, affected joint count, disease duration or medication. CONCLUSIONS: Elevated levels of destruction biomarkers in JIA compared to healthy children indicate a potential to serve as clinical tools for destructive joint disease. High levels of TRAP5b, NTX-I and collagen II in JIA in contrast to more pronounced aggrecan and COMP degradation in juvenile knee injuries, suggests that JIA patients have a unique biomarker pattern, different from healthy and knee-injured children.
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