Spinal disulfide HMGB1, but not all-thiol HMGB1, induces mechanical hypersensitivity in a TLR4-dependent manner

Spinal disulfide HMGB1, but not all-thiol HMGB1, induces mechanical hypersensitivity in a... Scandinavian Journal of Pain 8 (2015) 47–54Contents lists available at ScienceDirectScandinavian Journal of Painjournal homepage: www.ScandinavianJournalPain.comAbstracts from the Annual Scientific Meeting of the ScandinavianAssociation for the Study of PainSpinal disulfide HMGB1, but not all-thiolHMGB1, induces mechanical hypersensitivity ina TLR4-dependent mannerN.M. Agalave a,∗ , S. AbdelMoaty a , P. Lundback b ,U. Andersson b , H. Harris b , C.I. Svensson aaDepartment of Physiology and Pharmacology,Karolinska Institutet, Stockholm, Swedenb Department of Medicine, Karolinska Institutet,Stockholm, SwedenE-mail address: nilesh.agalave@ki.se(N.M. Agalave).Aims: Increasing evidence indicates that extracellular highmobility group box-1 protein (HMGB1) is involved in the pathogenesis of inflammatory and autoimmune disease. Data from ourlaboratory demonstrates that HMGB1 contributes to nociceptivebehavior in a model of rheumatoid arthritis-induced pain. HMGB1binds to multiple receptors, including toll like receptor (TLR) 2,TLR4 and receptor for advanced glycation end products (RAGE).When the cysteine in position C106 is in the reduced thiol form andC23 and C45 are engaged in a disulfide bridge (disulfide HMGB1),the molecule functions as a cytokine-inducing TLR4 ligand. In contrast, when these three cysteines are all reduced (all-thiol HMGB1),HMGB1 exclusively potentiates chemotactic activity via CXCR4. Itis currently not well understood which receptor and which redoxform of HMGB1 that mediates pain hypersensitivity and is thereforethe aim of this study.Method: All animal work was carried out in accordance withprotocol approved by the local ethics committee for animal experiments in Sweden. Balb/c, C57B/l6 (WT), Tlr2−/− , Tlr4−/− andRage−/− male mice were used for this study. Disulfide (ds) and allthiol (at) form of HMGB1 were injected intrathecally (1 ␮g) andmechanical hypersensitivity assessed by von Frey filaments. Lumbar spinal cords were collected after i.t. injection of atHMGB1 andds HMGB1 and mRNA levels for cytokine and glia markers assessedby quantitative PCR.Results: In Balb/c and C57Bl/6 WT mice, i.t injection ofdsHMGB1, but not atHMGB1, led to a significant reduction inmechanical thresholds. dsHMGB1 induced mechanical hypersensitivity 6 h after i.t. injection, which lasted for 5 days, comparedto i.t. injection of saline. When dsHMGB1 was injected i.t. to Tlr4DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2015.04.002.1877-8860/$ – see front matterdeficient mice it did not induce mechanical hypersensitivity. Incontrast Tlr2 and Rage deficient mice were still susceptible todsHMGB1-induced mechanical hypersensitivity. Analysis of mRNAfor cytokines and glial cell-associated factors in lumbar spinal cordsrevealed increased levels of Tnf, Ccl2, Cxcl1, Cxcl2, Gfap and Cd11b inmice injected with dsHMGB1, but not atHMGB1, with exception forIl1ˇ and Cxcr3 that was induced also by atHMGB1. Intrathecal injection of dsHMGB1 to Tlr4−/− deficient mice, did not increase mRNAlevels for Tnf, Il1ˇ, Ccl2, Gfap and Cd11b.Conclusions: We found the i.t. injection of the disulfide, but notthe all-thiol, form of HMGB1 to induce pronounced and long-lastingmechanical hypersensitivity, glial reactivity and cytokine induction in a TLR4-, but not TLR2- or RAGE-dependent manner. Thusour data indicates that, the redox state of HMGB1 is key for determining its nociceptive property and receptor usage and thus alsothe functional consequences of HMGB1 release. Agents interferingwith extracellular HMGB1 may be considered in the developmentof new pain relieving therapeutics.http://dx.doi.org/10.1016/j.sjpain.2015.04.004Practitioners’ perspective on pain disabilities inGhanaian women. A qualitative studyD. Ayim-Aboagye a,∗ , T. Gordh baWisconsin International University, Legon, Accra,Ghanab Multidisciplinary Pain Clinic, Uppsala UniversityHospital, Uppsala, SwedenE-mail addresses:ayim.aboagye.desmond@yahoo.com(D. Ayim-Aboagye), torsten.gordh@akademiska.se(T. Gordh).Aims: Women show higher frequency of most painful disorders.This is usually explained that endogenous pain modulation pathways, which affect incoming nociceptive signals, act differently inwomen and men, but psycho-social factors are likely to influence aswell. Ghanaian women suffer different disabilities that may lead tosevere pain. The hard climatic conditions and the hard physical toilin work exert untold injuries. How do women in Ghana cope withpainful disorders, and do they show certain behavioural patternduring diagnosis and treatments?Methods: The study used in-depth interviews with health careproviders to accomplish its aim. The “snowball effect” was added http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Scandinavian Journal of Pain de Gruyter

Spinal disulfide HMGB1, but not all-thiol HMGB1, induces mechanical hypersensitivity in a TLR4-dependent manner

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de Gruyter
Copyright
© 2015 Scandinavian Association for the Study of Pain
ISSN
1877-8860
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1877-8879
D.O.I.
10.1016/j.sjpain.2015.04.004
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Abstract

Scandinavian Journal of Pain 8 (2015) 47–54Contents lists available at ScienceDirectScandinavian Journal of Painjournal homepage: www.ScandinavianJournalPain.comAbstracts from the Annual Scientific Meeting of the ScandinavianAssociation for the Study of PainSpinal disulfide HMGB1, but not all-thiolHMGB1, induces mechanical hypersensitivity ina TLR4-dependent mannerN.M. Agalave a,∗ , S. AbdelMoaty a , P. Lundback b ,U. Andersson b , H. Harris b , C.I. Svensson aaDepartment of Physiology and Pharmacology,Karolinska Institutet, Stockholm, Swedenb Department of Medicine, Karolinska Institutet,Stockholm, SwedenE-mail address: nilesh.agalave@ki.se(N.M. Agalave).Aims: Increasing evidence indicates that extracellular highmobility group box-1 protein (HMGB1) is involved in the pathogenesis of inflammatory and autoimmune disease. Data from ourlaboratory demonstrates that HMGB1 contributes to nociceptivebehavior in a model of rheumatoid arthritis-induced pain. HMGB1binds to multiple receptors, including toll like receptor (TLR) 2,TLR4 and receptor for advanced glycation end products (RAGE).When the cysteine in position C106 is in the reduced thiol form andC23 and C45 are engaged in a disulfide bridge (disulfide HMGB1),the molecule functions as a cytokine-inducing TLR4 ligand. In contrast, when these three cysteines are all reduced (all-thiol HMGB1),HMGB1 exclusively potentiates chemotactic activity via CXCR4. Itis currently not well understood which receptor and which redoxform of HMGB1 that mediates pain hypersensitivity and is thereforethe aim of this study.Method: All animal work was carried out in accordance withprotocol approved by the local ethics committee for animal experiments in Sweden. Balb/c, C57B/l6 (WT), Tlr2−/− , Tlr4−/− andRage−/− male mice were used for this study. Disulfide (ds) and allthiol (at) form of HMGB1 were injected intrathecally (1 ␮g) andmechanical hypersensitivity assessed by von Frey filaments. Lumbar spinal cords were collected after i.t. injection of atHMGB1 andds HMGB1 and mRNA levels for cytokine and glia markers assessedby quantitative PCR.Results: In Balb/c and C57Bl/6 WT mice, i.t injection ofdsHMGB1, but not atHMGB1, led to a significant reduction inmechanical thresholds. dsHMGB1 induced mechanical hypersensitivity 6 h after i.t. injection, which lasted for 5 days, comparedto i.t. injection of saline. When dsHMGB1 was injected i.t. to Tlr4DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2015.04.002.1877-8860/$ – see front matterdeficient mice it did not induce mechanical hypersensitivity. Incontrast Tlr2 and Rage deficient mice were still susceptible todsHMGB1-induced mechanical hypersensitivity. Analysis of mRNAfor cytokines and glial cell-associated factors in lumbar spinal cordsrevealed increased levels of Tnf, Ccl2, Cxcl1, Cxcl2, Gfap and Cd11b inmice injected with dsHMGB1, but not atHMGB1, with exception forIl1ˇ and Cxcr3 that was induced also by atHMGB1. Intrathecal injection of dsHMGB1 to Tlr4−/− deficient mice, did not increase mRNAlevels for Tnf, Il1ˇ, Ccl2, Gfap and Cd11b.Conclusions: We found the i.t. injection of the disulfide, but notthe all-thiol, form of HMGB1 to induce pronounced and long-lastingmechanical hypersensitivity, glial reactivity and cytokine induction in a TLR4-, but not TLR2- or RAGE-dependent manner. Thusour data indicates that, the redox state of HMGB1 is key for determining its nociceptive property and receptor usage and thus alsothe functional consequences of HMGB1 release. Agents interferingwith extracellular HMGB1 may be considered in the developmentof new pain relieving therapeutics.http://dx.doi.org/10.1016/j.sjpain.2015.04.004Practitioners’ perspective on pain disabilities inGhanaian women. A qualitative studyD. Ayim-Aboagye a,∗ , T. Gordh baWisconsin International University, Legon, Accra,Ghanab Multidisciplinary Pain Clinic, Uppsala UniversityHospital, Uppsala, SwedenE-mail addresses:ayim.aboagye.desmond@yahoo.com(D. Ayim-Aboagye), torsten.gordh@akademiska.se(T. Gordh).Aims: Women show higher frequency of most painful disorders.This is usually explained that endogenous pain modulation pathways, which affect incoming nociceptive signals, act differently inwomen and men, but psycho-social factors are likely to influence aswell. Ghanaian women suffer different disabilities that may lead tosevere pain. The hard climatic conditions and the hard physical toilin work exert untold injuries. How do women in Ghana cope withpainful disorders, and do they show certain behavioural patternduring diagnosis and treatments?Methods: The study used in-depth interviews with health careproviders to accomplish its aim. The “snowball effect” was added

Journal

Scandinavian Journal of Painde Gruyter

Published: Jul 1, 2015

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