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Wade S. Kingery - One of the best experts on this subject based on the ideXlab platform.

  • il 6 signaling mediates the germinal center response igm production and nociceptive sensitization in male mice after Tibia Fracture
    Brain Behavior and Immunity, 2021
    Co-Authors: Yang Yang, David J Clark, Wade S. Kingery, Tian-zhi Guo, Xiaoyou Shi, Peyman Sahbaie, Qin Guang, Leonore A Herzenberg
    Abstract:

    Abstract Background Up-regulated interleukin 6 (IL-6) signaling, immune system activation, and pronociceptive autoantibodies are characteristic of complex regional pain syndrome (CRPS). IL-6 is known to promote B cell differentiation, thus we hypothesized that IL-6 signaling plays a crucial role in the development of adaptive immune responses and nociceptive sensitization in a murine Tibia Fracture model of CRPS. Methods Mice deficient in IL-6 expression (IL-6−/−) or B cell deficient (muMT) underwent Tibia Fracture and 3 weeks of cast immobilization or sham injury. The deposition of IgM in Fractured limbs was followed using Western blotting, and passive serum transfer to muMT Fracture mice was used to detect nociception-supporting autoantibodies. Lymph nodes were assessed for hypertrophy, IL-6 expression was measured using qPCR and ELISA, and germinal center formation was evaluated using FACS and immunohistochemistry. The therapeutic effects of exogenous neutralizing anti-IL-6 antibodies were also evaluated in the CRPS Fracture model. Results Functional IL-6 signaling was required for the post Fracture development of nociceptive sensitization, vascular changes, and IgM immune complex deposition in the skin of injured limbs. Passive transfer of sera from wild-type, but not IL-6−/− Fracture mice into muMT Fracture mice caused enhanced allodynia and postural unweighting. IL-6−/− Fracture mice displayed reduced popliteal lymphadenopathy after Fracture. Germinal center responses were detected in the popliteal lymph nodes of wild-type, but not in IL-6−/− Fracture mice. We observed that IL-6 expression was dramatically enhanced in popliteal lymph node tissue after Fracture. Conversely, administration of anti-IL-6 antibodies reduced nociceptive and vascular changes after Fracture and inhibited lymphadenopathy. Conclusions Collectively, these data support the hypothesis that IL-6 signaling in the Fracture limb of mice is required for germinal center formation, IgM autoantibody production and nociceptive sensitization. Anti-IL-6 therapies might, therefore, reduce pain after limb Fracture or in the setting of CRPS.

  • germinal center formation immunoglobulin production and hindlimb nociceptive sensitization after Tibia Fracture
    Brain Behavior and Immunity, 2020
    Co-Authors: Yang Yang, Wade S. Kingery, Tian-zhi Guo, Xiaoyou Shi, Qin Guang, Leonore A Herzenberg, David J Clark
    Abstract:

    Abstract Emerging evidence suggests that Complex Regional Pain Syndrome (CRPS) is in part a post-traumatic autoimmune disease mediated by an adaptive immune response after limb injuries. We previously observed in a murine Tibial Fracture model of CRPS that pain-related behaviors were dependent upon adaptive immune mechanisms including the neuropeptide-dependent production of IgM for 5 months after injury. However, the time course of induction of this immune response and the demonstration of germinal center formation in lymphoid organs has not been evaluated. Using the murine Fracture model, we employed behavioral tests of nociceptive sensitization and limb dysfunction, serum passive transfer techniques, western blot analysis of IgM accumulation, fluorescence-activated cell sorting (FACS) of lymphoid tissues and immunohistochemistry to follow the temporal activation of the adaptive immune response over the first 3 weeks after Fracture. We observed that: 1) IgM protein levels in the skin of the Fractured mice were elevated at 3 weeks post Fracture, but not at earlier time points, 2) serum from Fracture mice at 3 weeks, but not 1 and 2 weeks post Fracture, had pro-nociceptive effects when passively transferred to Fractured muMT mice lacking B cells, 3) Fracture induced popliteal lymphadenopathy occurred ipsilateral to Fracture beginning at 1 week and peaking at 3 weeks post Fracture, 4) a germinal center reaction was detected by FACS analysis in the popliteal lymph nodes from injured limbs by 3 weeks post Fracture but not in other lymphoid tissues, 5) germinal center formation was characterized by the induction of T follicular helper cells (Tfh) and germinal center B cells in the popliteal lymph nodes of the injured but not contralateral limbs, and 6) Fracture mice treated with the Tfh signaling inhibitor FK506 had impaired germinal center reactions, reduced IgM levels, reduced nociceptive sensitization, and no pronociceptive serum effects after administration to Fractured muMT mice. Collectively these data demonstrate that Tibia Fracture induces an adaptive autoimmune response characterized by popliteal lymph node germinal center formation and Tfh cell dependent B cell activation, resulting in nociceptive sensitization within 3 weeks.

  • sex differences in the temporal development of pronociceptive immune responses in the Tibia Fracture mouse model
    Pain, 2019
    Co-Authors: Tian-zhi Guo, David J Clark, Xiaoyou Shi, Tzuping Wei, Wade S. Kingery
    Abstract:

    Previously, distinct sex differences were observed in the pronociceptive role of spinal immune cells in neuropathic and inflammatory mouse pain models. Both peripheral and central innate and adaptive immune changes contribute to sensitization in the Tibia Fracture rodent model of complex regional pain syndrome, and the current study evaluated sex differences in the development of pronociceptive immune responses after Fracture. At 4 and 7 weeks after Fracture, the analgesic effects of a microglia inhibitor were tested in male and female mice, and polymerase chain reaction was used to measure inflammatory mediator expression in skin and spinal cord. The temporal progression of complex regional pain syndrome-like changes in male and female wild-type and muMT Fracture mice lacking B cells and antibodies were evaluated, and IgM antibody deposition measured. Pronociceptive effects of injecting wild-type Fracture mouse serum into muMT Fracture mice were also tested in both sexes, and the role of sex hormones was evaluated in the postFracture development of pronociceptive immune responses. Long-lasting immune changes developed in the Fracture limb and corresponding spinal cord of both male and female mice, including upregulated neuropeptide and cytokine signaling, microglial activation, and pronociceptive autoimmunity. These complex postFracture immune responses were sexually dichotomous and interacted in temporally evolving patterns that generated post-traumatic nociceptive sensitization in both sexes lasting for up to 5 months. Unfortunately, the redundancy and plasticity of these chronic post-traumatic immune responses suggest that clinical interventions focusing on any single specific pronociceptive immune change are likely to be ineffectual.

  • the rodent Tibia Fracture model a critical review and comparison with the complex regional pain syndrome literature
    The Journal of Pain, 2018
    Co-Authors: Frank Birklein, Tanja Schlereth, Alaa Ibrahim, Wade S. Kingery
    Abstract:

    Abstract Distal limb Fracture is the most common cause of complex regional pain syndrome (CRPS), thus the rodent Tibia Fracture model (TFM) was developed to study CRPS pathogenesis. This comprehensive review summarizes the published TFM research and compares these experimental results with the CRPS literature. The TFM generated spontaneous and evoked pain behaviors, inflammatory symptoms (edema, warmth), and trophic changes (skin thickening, osteoporosis) resembling symptoms in early CRPS. Neuropeptides, inflammatory cytokines, and nerve growth factor (NGF) have been linked to pain behaviors, inflammation, and trophic changes in the TFM model and proliferating keratinocytes were identified as the primary source of cutaneous cytokines and NGF. Tibia Fracture also activated spinal glia and upregulated spinal neuropeptide, cytokine, and NGF expression, and in the brain it changed dendritic architecture. B cell-expressed immunoglobulin M antibodies also contributed to pain behavior, indicating a role for adaptive immunity. These results modeled many findings in early CRPS, but significant differences were also noted. Perspective Multiple neuroimmune signaling mechanisms contribute to the pain, inflammation, and trophic changes observed in the injured limb of the rodent TFM. This model replicates many of the symptoms, signs, and pathophysiology of early CRPS, but most post-Fracture changes resolve within 5 months and may not contribute to perpetuating chronic CRPS.

  • exercise reverses nociceptive sensitization upregulated neuropeptide signaling inflammatory changes anxiety and memory impairment in a mouse Tibia Fracture model
    Anesthesiology, 2018
    Co-Authors: Xiaoyou Shi, David J Clark, Tian-zhi Guo, Peyman Sahbaie, Kenner C. Rice, Agnieszka Sulima, Wade S. Kingery
    Abstract:

    What we already know about this topic WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: This study tested the hypothesis that ad lib running wheel exercise in a Tibia Fracture model of complex regional pain syndrome can reverse hindlimb nociceptive sensitization and inflammation in mice. Methods Three weeks after Tibia Fracture, the cast was removed and hindlimb von Frey thresholds and unweighting were tested; the mice were then randomized to either ad lib access to a running wheel for 4 weeks or no wheel access. After 4 weeks the behavioral testing was repeated and then skin, sciatic nerve, and spinal cord tissues collected for polymerase chain reaction and enzyme immunoassay measurements of neuropeptide and inflammatory mediator levels. A similar protocol was used in Fracture mice treated with exercise for 4 weeks, and then the running wheel was removed for 2 weeks. Memory and anxiety were measured in both groups with use of open-field, zero-maze, and novel-objects recognition assays. Results At 7 weeks postFracture the mice with no wheel access exhibited hindlimb allodynia and unweighting, anxiety, memory loss, upregulated spinal neuropeptide signaling, and increased hind paw and spinal inflammatory mediator expression, but the postFracture mice allowed to exercise for 4 weeks exhibited none of these changes (n = 12/cohort). When exercise was stopped for 2 weeks after 4 weeks of running, hindlimb allodynia and unweighting were rekindled, and this nociceptive sensitization was associated with increased sciatic nerve neuropeptide levels and hind paw skin interleukin 6 and nerve growth factor expression (n = 12/cohort). Conclusions Daily exercise reversed nociceptive sensitization, inflammation, anxiety, and memory loss after Tibia Fracture.

David J Clark - One of the best experts on this subject based on the ideXlab platform.

  • circulating micrornas from the mouse Tibia Fracture model reflect the signature from patients with complex regional pain syndrome
    Pattern Recognition, 2021
    Co-Authors: Jason R Wickman, David J Clark, Peyman Sahbaie, Xuan Luo, Renee Jeantoussaint, Ahmet Sacan, Seena K Ajit
    Abstract:

    Introduction Complex regional pain syndrome (CRPS) often results from an initial trauma that later produces a disproportionate amount of pain. The mechanisms underlying CRPS have been studied using a Tibia Fracture model (TFM) in rodents because this model closely mimics symptoms and has several molecular correlates observed in patients with CRPS. Objective Here, we determined whether the TFM has alterations in circulating microRNAs (miRNAs) and cytokines transported by small extracellular vesicles (sEVs) that faithfully model previously reported miRNA alterations from patients with CRPS. Methods We isolated and characterized serum-derived sEVs from mice 3 weeks after Fracture when symptoms such as pain hypersensitivity develop. Whole-transcriptome profiling was used to determine sEV miRNAs, and Bio-Plex Pro Mouse Cytokine 23-plex assay was used to measure cytokines. Differentially expressed miRNAs from TFM were compared with previously reported circulating miRNA alterations from patients with CRPS. Results Although sEV cytokine levels were unchanged, there were significant changes in sEV miRNA profiles. Differentially expressed miRNAs from TFM sEVs significantly overlapped with those previously reported in patients with CRPS. Of the 57 sEV miRNAs dysregulated in the TFM, 30 were previously reported in patients with CRPS compared with healthy control donors both in sEVs and 23 in whole blood. Conclusions These findings enhance the validity of TFM as a model for CRPS and suggest that specific miRNA dysregulation may be a shared feature of CRPS and the TFM. These dysregulated miRNAs could help identify mechanistic targets or serve as biomarker candidates for both diagnosis and treatment responses in clinical trials.

  • il 6 signaling mediates the germinal center response igm production and nociceptive sensitization in male mice after Tibia Fracture
    Brain Behavior and Immunity, 2021
    Co-Authors: Yang Yang, David J Clark, Wade S. Kingery, Tian-zhi Guo, Xiaoyou Shi, Peyman Sahbaie, Qin Guang, Leonore A Herzenberg
    Abstract:

    Abstract Background Up-regulated interleukin 6 (IL-6) signaling, immune system activation, and pronociceptive autoantibodies are characteristic of complex regional pain syndrome (CRPS). IL-6 is known to promote B cell differentiation, thus we hypothesized that IL-6 signaling plays a crucial role in the development of adaptive immune responses and nociceptive sensitization in a murine Tibia Fracture model of CRPS. Methods Mice deficient in IL-6 expression (IL-6−/−) or B cell deficient (muMT) underwent Tibia Fracture and 3 weeks of cast immobilization or sham injury. The deposition of IgM in Fractured limbs was followed using Western blotting, and passive serum transfer to muMT Fracture mice was used to detect nociception-supporting autoantibodies. Lymph nodes were assessed for hypertrophy, IL-6 expression was measured using qPCR and ELISA, and germinal center formation was evaluated using FACS and immunohistochemistry. The therapeutic effects of exogenous neutralizing anti-IL-6 antibodies were also evaluated in the CRPS Fracture model. Results Functional IL-6 signaling was required for the post Fracture development of nociceptive sensitization, vascular changes, and IgM immune complex deposition in the skin of injured limbs. Passive transfer of sera from wild-type, but not IL-6−/− Fracture mice into muMT Fracture mice caused enhanced allodynia and postural unweighting. IL-6−/− Fracture mice displayed reduced popliteal lymphadenopathy after Fracture. Germinal center responses were detected in the popliteal lymph nodes of wild-type, but not in IL-6−/− Fracture mice. We observed that IL-6 expression was dramatically enhanced in popliteal lymph node tissue after Fracture. Conversely, administration of anti-IL-6 antibodies reduced nociceptive and vascular changes after Fracture and inhibited lymphadenopathy. Conclusions Collectively, these data support the hypothesis that IL-6 signaling in the Fracture limb of mice is required for germinal center formation, IgM autoantibody production and nociceptive sensitization. Anti-IL-6 therapies might, therefore, reduce pain after limb Fracture or in the setting of CRPS.

  • germinal center formation immunoglobulin production and hindlimb nociceptive sensitization after Tibia Fracture
    Brain Behavior and Immunity, 2020
    Co-Authors: Yang Yang, Wade S. Kingery, Tian-zhi Guo, Xiaoyou Shi, Qin Guang, Leonore A Herzenberg, David J Clark
    Abstract:

    Abstract Emerging evidence suggests that Complex Regional Pain Syndrome (CRPS) is in part a post-traumatic autoimmune disease mediated by an adaptive immune response after limb injuries. We previously observed in a murine Tibial Fracture model of CRPS that pain-related behaviors were dependent upon adaptive immune mechanisms including the neuropeptide-dependent production of IgM for 5 months after injury. However, the time course of induction of this immune response and the demonstration of germinal center formation in lymphoid organs has not been evaluated. Using the murine Fracture model, we employed behavioral tests of nociceptive sensitization and limb dysfunction, serum passive transfer techniques, western blot analysis of IgM accumulation, fluorescence-activated cell sorting (FACS) of lymphoid tissues and immunohistochemistry to follow the temporal activation of the adaptive immune response over the first 3 weeks after Fracture. We observed that: 1) IgM protein levels in the skin of the Fractured mice were elevated at 3 weeks post Fracture, but not at earlier time points, 2) serum from Fracture mice at 3 weeks, but not 1 and 2 weeks post Fracture, had pro-nociceptive effects when passively transferred to Fractured muMT mice lacking B cells, 3) Fracture induced popliteal lymphadenopathy occurred ipsilateral to Fracture beginning at 1 week and peaking at 3 weeks post Fracture, 4) a germinal center reaction was detected by FACS analysis in the popliteal lymph nodes from injured limbs by 3 weeks post Fracture but not in other lymphoid tissues, 5) germinal center formation was characterized by the induction of T follicular helper cells (Tfh) and germinal center B cells in the popliteal lymph nodes of the injured but not contralateral limbs, and 6) Fracture mice treated with the Tfh signaling inhibitor FK506 had impaired germinal center reactions, reduced IgM levels, reduced nociceptive sensitization, and no pronociceptive serum effects after administration to Fractured muMT mice. Collectively these data demonstrate that Tibia Fracture induces an adaptive autoimmune response characterized by popliteal lymph node germinal center formation and Tfh cell dependent B cell activation, resulting in nociceptive sensitization within 3 weeks.

  • complex regional pain syndrome patient immunoglobulin m has pronociceptive effects in the skin and spinal cord of Tibia Fracture mice
    Pain, 2020
    Co-Authors: Tian-zhi Guo, David J Clark, Frank Birklein, Tzuping Wei, Maral Tajerian, Andreas Goebel, Peyman Sahbaie, Fabiola L Escolano, Myriam Herrnberger
    Abstract:

    It has been proposed that complex regional pain syndrome (CRPS) is a post-traumatic autoimmune disease. Previously, we observed that B cells are required for the full expression of CRPS-like changes in a mouse Tibia Fracture model and that serum immunoglobulin M (IgM) antibodies from Fracture mice have pronociceptive effects in muMT Fracture mice lacking B cells. The current study evaluated the pronociceptive effects of injecting CRPS patient serum or antibodies into muMT Fracture mice by measuring hind paw allodynia and unweighting changes. Complex regional pain syndrome serum binding was measured against autoantigens previously identified in the Fracture mouse model. Both CRPS patient serum or IgM antibodies had pronociceptive effects in the Fracture limb when injected systemically in muMT Fracture mice, but normal subject serum and CRPS patient IgG antibodies had no effect. Furthermore, CRPS serum IgM antibodies had pronociceptive effects when injected into the Fracture limb hind paw skin or intrathecally in the muMT Fracture mice. Early (1-12 months after injury) CRPS patient (n = 20) sera were always pronociceptive after systemic injection, and chronic (>12 months after injury) CRPS sera were rarely pronociceptive (2/20 patients), while sera from normal subjects (n = 20) and from patients with uncomplicated recoveries from orthopedic surgery and/or Fracture (n = 15) were never pronociceptive. Increased CRPS serum IgM binding was observed for keratin 16, histone 3.2, gamma actin, and alpha enolase autoantigens. We postulate that CRPS patient IgM antibodies bind to neoantigens in the Fracture mouse skin and spinal cord to initiate a regionally restricted pronociceptive complement response potentially contributing to the CRPS disease process.

  • sex differences in the temporal development of pronociceptive immune responses in the Tibia Fracture mouse model
    Pain, 2019
    Co-Authors: Tian-zhi Guo, David J Clark, Xiaoyou Shi, Tzuping Wei, Wade S. Kingery
    Abstract:

    Previously, distinct sex differences were observed in the pronociceptive role of spinal immune cells in neuropathic and inflammatory mouse pain models. Both peripheral and central innate and adaptive immune changes contribute to sensitization in the Tibia Fracture rodent model of complex regional pain syndrome, and the current study evaluated sex differences in the development of pronociceptive immune responses after Fracture. At 4 and 7 weeks after Fracture, the analgesic effects of a microglia inhibitor were tested in male and female mice, and polymerase chain reaction was used to measure inflammatory mediator expression in skin and spinal cord. The temporal progression of complex regional pain syndrome-like changes in male and female wild-type and muMT Fracture mice lacking B cells and antibodies were evaluated, and IgM antibody deposition measured. Pronociceptive effects of injecting wild-type Fracture mouse serum into muMT Fracture mice were also tested in both sexes, and the role of sex hormones was evaluated in the postFracture development of pronociceptive immune responses. Long-lasting immune changes developed in the Fracture limb and corresponding spinal cord of both male and female mice, including upregulated neuropeptide and cytokine signaling, microglial activation, and pronociceptive autoimmunity. These complex postFracture immune responses were sexually dichotomous and interacted in temporally evolving patterns that generated post-traumatic nociceptive sensitization in both sexes lasting for up to 5 months. Unfortunately, the redundancy and plasticity of these chronic post-traumatic immune responses suggest that clinical interventions focusing on any single specific pronociceptive immune change are likely to be ineffectual.

Tian-zhi Guo - One of the best experts on this subject based on the ideXlab platform.

  • il 6 signaling mediates the germinal center response igm production and nociceptive sensitization in male mice after Tibia Fracture
    Brain Behavior and Immunity, 2021
    Co-Authors: Yang Yang, David J Clark, Wade S. Kingery, Tian-zhi Guo, Xiaoyou Shi, Peyman Sahbaie, Qin Guang, Leonore A Herzenberg
    Abstract:

    Abstract Background Up-regulated interleukin 6 (IL-6) signaling, immune system activation, and pronociceptive autoantibodies are characteristic of complex regional pain syndrome (CRPS). IL-6 is known to promote B cell differentiation, thus we hypothesized that IL-6 signaling plays a crucial role in the development of adaptive immune responses and nociceptive sensitization in a murine Tibia Fracture model of CRPS. Methods Mice deficient in IL-6 expression (IL-6−/−) or B cell deficient (muMT) underwent Tibia Fracture and 3 weeks of cast immobilization or sham injury. The deposition of IgM in Fractured limbs was followed using Western blotting, and passive serum transfer to muMT Fracture mice was used to detect nociception-supporting autoantibodies. Lymph nodes were assessed for hypertrophy, IL-6 expression was measured using qPCR and ELISA, and germinal center formation was evaluated using FACS and immunohistochemistry. The therapeutic effects of exogenous neutralizing anti-IL-6 antibodies were also evaluated in the CRPS Fracture model. Results Functional IL-6 signaling was required for the post Fracture development of nociceptive sensitization, vascular changes, and IgM immune complex deposition in the skin of injured limbs. Passive transfer of sera from wild-type, but not IL-6−/− Fracture mice into muMT Fracture mice caused enhanced allodynia and postural unweighting. IL-6−/− Fracture mice displayed reduced popliteal lymphadenopathy after Fracture. Germinal center responses were detected in the popliteal lymph nodes of wild-type, but not in IL-6−/− Fracture mice. We observed that IL-6 expression was dramatically enhanced in popliteal lymph node tissue after Fracture. Conversely, administration of anti-IL-6 antibodies reduced nociceptive and vascular changes after Fracture and inhibited lymphadenopathy. Conclusions Collectively, these data support the hypothesis that IL-6 signaling in the Fracture limb of mice is required for germinal center formation, IgM autoantibody production and nociceptive sensitization. Anti-IL-6 therapies might, therefore, reduce pain after limb Fracture or in the setting of CRPS.

  • germinal center formation immunoglobulin production and hindlimb nociceptive sensitization after Tibia Fracture
    Brain Behavior and Immunity, 2020
    Co-Authors: Yang Yang, Wade S. Kingery, Tian-zhi Guo, Xiaoyou Shi, Qin Guang, Leonore A Herzenberg, David J Clark
    Abstract:

    Abstract Emerging evidence suggests that Complex Regional Pain Syndrome (CRPS) is in part a post-traumatic autoimmune disease mediated by an adaptive immune response after limb injuries. We previously observed in a murine Tibial Fracture model of CRPS that pain-related behaviors were dependent upon adaptive immune mechanisms including the neuropeptide-dependent production of IgM for 5 months after injury. However, the time course of induction of this immune response and the demonstration of germinal center formation in lymphoid organs has not been evaluated. Using the murine Fracture model, we employed behavioral tests of nociceptive sensitization and limb dysfunction, serum passive transfer techniques, western blot analysis of IgM accumulation, fluorescence-activated cell sorting (FACS) of lymphoid tissues and immunohistochemistry to follow the temporal activation of the adaptive immune response over the first 3 weeks after Fracture. We observed that: 1) IgM protein levels in the skin of the Fractured mice were elevated at 3 weeks post Fracture, but not at earlier time points, 2) serum from Fracture mice at 3 weeks, but not 1 and 2 weeks post Fracture, had pro-nociceptive effects when passively transferred to Fractured muMT mice lacking B cells, 3) Fracture induced popliteal lymphadenopathy occurred ipsilateral to Fracture beginning at 1 week and peaking at 3 weeks post Fracture, 4) a germinal center reaction was detected by FACS analysis in the popliteal lymph nodes from injured limbs by 3 weeks post Fracture but not in other lymphoid tissues, 5) germinal center formation was characterized by the induction of T follicular helper cells (Tfh) and germinal center B cells in the popliteal lymph nodes of the injured but not contralateral limbs, and 6) Fracture mice treated with the Tfh signaling inhibitor FK506 had impaired germinal center reactions, reduced IgM levels, reduced nociceptive sensitization, and no pronociceptive serum effects after administration to Fractured muMT mice. Collectively these data demonstrate that Tibia Fracture induces an adaptive autoimmune response characterized by popliteal lymph node germinal center formation and Tfh cell dependent B cell activation, resulting in nociceptive sensitization within 3 weeks.

  • complex regional pain syndrome patient immunoglobulin m has pronociceptive effects in the skin and spinal cord of Tibia Fracture mice
    Pain, 2020
    Co-Authors: Tian-zhi Guo, David J Clark, Frank Birklein, Tzuping Wei, Maral Tajerian, Andreas Goebel, Peyman Sahbaie, Fabiola L Escolano, Myriam Herrnberger
    Abstract:

    It has been proposed that complex regional pain syndrome (CRPS) is a post-traumatic autoimmune disease. Previously, we observed that B cells are required for the full expression of CRPS-like changes in a mouse Tibia Fracture model and that serum immunoglobulin M (IgM) antibodies from Fracture mice have pronociceptive effects in muMT Fracture mice lacking B cells. The current study evaluated the pronociceptive effects of injecting CRPS patient serum or antibodies into muMT Fracture mice by measuring hind paw allodynia and unweighting changes. Complex regional pain syndrome serum binding was measured against autoantigens previously identified in the Fracture mouse model. Both CRPS patient serum or IgM antibodies had pronociceptive effects in the Fracture limb when injected systemically in muMT Fracture mice, but normal subject serum and CRPS patient IgG antibodies had no effect. Furthermore, CRPS serum IgM antibodies had pronociceptive effects when injected into the Fracture limb hind paw skin or intrathecally in the muMT Fracture mice. Early (1-12 months after injury) CRPS patient (n = 20) sera were always pronociceptive after systemic injection, and chronic (>12 months after injury) CRPS sera were rarely pronociceptive (2/20 patients), while sera from normal subjects (n = 20) and from patients with uncomplicated recoveries from orthopedic surgery and/or Fracture (n = 15) were never pronociceptive. Increased CRPS serum IgM binding was observed for keratin 16, histone 3.2, gamma actin, and alpha enolase autoantigens. We postulate that CRPS patient IgM antibodies bind to neoantigens in the Fracture mouse skin and spinal cord to initiate a regionally restricted pronociceptive complement response potentially contributing to the CRPS disease process.

  • sex differences in the temporal development of pronociceptive immune responses in the Tibia Fracture mouse model
    Pain, 2019
    Co-Authors: Tian-zhi Guo, David J Clark, Xiaoyou Shi, Tzuping Wei, Wade S. Kingery
    Abstract:

    Previously, distinct sex differences were observed in the pronociceptive role of spinal immune cells in neuropathic and inflammatory mouse pain models. Both peripheral and central innate and adaptive immune changes contribute to sensitization in the Tibia Fracture rodent model of complex regional pain syndrome, and the current study evaluated sex differences in the development of pronociceptive immune responses after Fracture. At 4 and 7 weeks after Fracture, the analgesic effects of a microglia inhibitor were tested in male and female mice, and polymerase chain reaction was used to measure inflammatory mediator expression in skin and spinal cord. The temporal progression of complex regional pain syndrome-like changes in male and female wild-type and muMT Fracture mice lacking B cells and antibodies were evaluated, and IgM antibody deposition measured. Pronociceptive effects of injecting wild-type Fracture mouse serum into muMT Fracture mice were also tested in both sexes, and the role of sex hormones was evaluated in the postFracture development of pronociceptive immune responses. Long-lasting immune changes developed in the Fracture limb and corresponding spinal cord of both male and female mice, including upregulated neuropeptide and cytokine signaling, microglial activation, and pronociceptive autoimmunity. These complex postFracture immune responses were sexually dichotomous and interacted in temporally evolving patterns that generated post-traumatic nociceptive sensitization in both sexes lasting for up to 5 months. Unfortunately, the redundancy and plasticity of these chronic post-traumatic immune responses suggest that clinical interventions focusing on any single specific pronociceptive immune change are likely to be ineffectual.

  • exercise reverses nociceptive sensitization upregulated neuropeptide signaling inflammatory changes anxiety and memory impairment in a mouse Tibia Fracture model
    Anesthesiology, 2018
    Co-Authors: Xiaoyou Shi, David J Clark, Tian-zhi Guo, Peyman Sahbaie, Kenner C. Rice, Agnieszka Sulima, Wade S. Kingery
    Abstract:

    What we already know about this topic WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: This study tested the hypothesis that ad lib running wheel exercise in a Tibia Fracture model of complex regional pain syndrome can reverse hindlimb nociceptive sensitization and inflammation in mice. Methods Three weeks after Tibia Fracture, the cast was removed and hindlimb von Frey thresholds and unweighting were tested; the mice were then randomized to either ad lib access to a running wheel for 4 weeks or no wheel access. After 4 weeks the behavioral testing was repeated and then skin, sciatic nerve, and spinal cord tissues collected for polymerase chain reaction and enzyme immunoassay measurements of neuropeptide and inflammatory mediator levels. A similar protocol was used in Fracture mice treated with exercise for 4 weeks, and then the running wheel was removed for 2 weeks. Memory and anxiety were measured in both groups with use of open-field, zero-maze, and novel-objects recognition assays. Results At 7 weeks postFracture the mice with no wheel access exhibited hindlimb allodynia and unweighting, anxiety, memory loss, upregulated spinal neuropeptide signaling, and increased hind paw and spinal inflammatory mediator expression, but the postFracture mice allowed to exercise for 4 weeks exhibited none of these changes (n = 12/cohort). When exercise was stopped for 2 weeks after 4 weeks of running, hindlimb allodynia and unweighting were rekindled, and this nociceptive sensitization was associated with increased sciatic nerve neuropeptide levels and hind paw skin interleukin 6 and nerve growth factor expression (n = 12/cohort). Conclusions Daily exercise reversed nociceptive sensitization, inflammation, anxiety, and memory loss after Tibia Fracture.

Xiaoyou Shi - One of the best experts on this subject based on the ideXlab platform.

  • il 6 signaling mediates the germinal center response igm production and nociceptive sensitization in male mice after Tibia Fracture
    Brain Behavior and Immunity, 2021
    Co-Authors: Yang Yang, David J Clark, Wade S. Kingery, Tian-zhi Guo, Xiaoyou Shi, Peyman Sahbaie, Qin Guang, Leonore A Herzenberg
    Abstract:

    Abstract Background Up-regulated interleukin 6 (IL-6) signaling, immune system activation, and pronociceptive autoantibodies are characteristic of complex regional pain syndrome (CRPS). IL-6 is known to promote B cell differentiation, thus we hypothesized that IL-6 signaling plays a crucial role in the development of adaptive immune responses and nociceptive sensitization in a murine Tibia Fracture model of CRPS. Methods Mice deficient in IL-6 expression (IL-6−/−) or B cell deficient (muMT) underwent Tibia Fracture and 3 weeks of cast immobilization or sham injury. The deposition of IgM in Fractured limbs was followed using Western blotting, and passive serum transfer to muMT Fracture mice was used to detect nociception-supporting autoantibodies. Lymph nodes were assessed for hypertrophy, IL-6 expression was measured using qPCR and ELISA, and germinal center formation was evaluated using FACS and immunohistochemistry. The therapeutic effects of exogenous neutralizing anti-IL-6 antibodies were also evaluated in the CRPS Fracture model. Results Functional IL-6 signaling was required for the post Fracture development of nociceptive sensitization, vascular changes, and IgM immune complex deposition in the skin of injured limbs. Passive transfer of sera from wild-type, but not IL-6−/− Fracture mice into muMT Fracture mice caused enhanced allodynia and postural unweighting. IL-6−/− Fracture mice displayed reduced popliteal lymphadenopathy after Fracture. Germinal center responses were detected in the popliteal lymph nodes of wild-type, but not in IL-6−/− Fracture mice. We observed that IL-6 expression was dramatically enhanced in popliteal lymph node tissue after Fracture. Conversely, administration of anti-IL-6 antibodies reduced nociceptive and vascular changes after Fracture and inhibited lymphadenopathy. Conclusions Collectively, these data support the hypothesis that IL-6 signaling in the Fracture limb of mice is required for germinal center formation, IgM autoantibody production and nociceptive sensitization. Anti-IL-6 therapies might, therefore, reduce pain after limb Fracture or in the setting of CRPS.

  • germinal center formation immunoglobulin production and hindlimb nociceptive sensitization after Tibia Fracture
    Brain Behavior and Immunity, 2020
    Co-Authors: Yang Yang, Wade S. Kingery, Tian-zhi Guo, Xiaoyou Shi, Qin Guang, Leonore A Herzenberg, David J Clark
    Abstract:

    Abstract Emerging evidence suggests that Complex Regional Pain Syndrome (CRPS) is in part a post-traumatic autoimmune disease mediated by an adaptive immune response after limb injuries. We previously observed in a murine Tibial Fracture model of CRPS that pain-related behaviors were dependent upon adaptive immune mechanisms including the neuropeptide-dependent production of IgM for 5 months after injury. However, the time course of induction of this immune response and the demonstration of germinal center formation in lymphoid organs has not been evaluated. Using the murine Fracture model, we employed behavioral tests of nociceptive sensitization and limb dysfunction, serum passive transfer techniques, western blot analysis of IgM accumulation, fluorescence-activated cell sorting (FACS) of lymphoid tissues and immunohistochemistry to follow the temporal activation of the adaptive immune response over the first 3 weeks after Fracture. We observed that: 1) IgM protein levels in the skin of the Fractured mice were elevated at 3 weeks post Fracture, but not at earlier time points, 2) serum from Fracture mice at 3 weeks, but not 1 and 2 weeks post Fracture, had pro-nociceptive effects when passively transferred to Fractured muMT mice lacking B cells, 3) Fracture induced popliteal lymphadenopathy occurred ipsilateral to Fracture beginning at 1 week and peaking at 3 weeks post Fracture, 4) a germinal center reaction was detected by FACS analysis in the popliteal lymph nodes from injured limbs by 3 weeks post Fracture but not in other lymphoid tissues, 5) germinal center formation was characterized by the induction of T follicular helper cells (Tfh) and germinal center B cells in the popliteal lymph nodes of the injured but not contralateral limbs, and 6) Fracture mice treated with the Tfh signaling inhibitor FK506 had impaired germinal center reactions, reduced IgM levels, reduced nociceptive sensitization, and no pronociceptive serum effects after administration to Fractured muMT mice. Collectively these data demonstrate that Tibia Fracture induces an adaptive autoimmune response characterized by popliteal lymph node germinal center formation and Tfh cell dependent B cell activation, resulting in nociceptive sensitization within 3 weeks.

  • sex differences in the temporal development of pronociceptive immune responses in the Tibia Fracture mouse model
    Pain, 2019
    Co-Authors: Tian-zhi Guo, David J Clark, Xiaoyou Shi, Tzuping Wei, Wade S. Kingery
    Abstract:

    Previously, distinct sex differences were observed in the pronociceptive role of spinal immune cells in neuropathic and inflammatory mouse pain models. Both peripheral and central innate and adaptive immune changes contribute to sensitization in the Tibia Fracture rodent model of complex regional pain syndrome, and the current study evaluated sex differences in the development of pronociceptive immune responses after Fracture. At 4 and 7 weeks after Fracture, the analgesic effects of a microglia inhibitor were tested in male and female mice, and polymerase chain reaction was used to measure inflammatory mediator expression in skin and spinal cord. The temporal progression of complex regional pain syndrome-like changes in male and female wild-type and muMT Fracture mice lacking B cells and antibodies were evaluated, and IgM antibody deposition measured. Pronociceptive effects of injecting wild-type Fracture mouse serum into muMT Fracture mice were also tested in both sexes, and the role of sex hormones was evaluated in the postFracture development of pronociceptive immune responses. Long-lasting immune changes developed in the Fracture limb and corresponding spinal cord of both male and female mice, including upregulated neuropeptide and cytokine signaling, microglial activation, and pronociceptive autoimmunity. These complex postFracture immune responses were sexually dichotomous and interacted in temporally evolving patterns that generated post-traumatic nociceptive sensitization in both sexes lasting for up to 5 months. Unfortunately, the redundancy and plasticity of these chronic post-traumatic immune responses suggest that clinical interventions focusing on any single specific pronociceptive immune change are likely to be ineffectual.

  • exercise reverses nociceptive sensitization upregulated neuropeptide signaling inflammatory changes anxiety and memory impairment in a mouse Tibia Fracture model
    Anesthesiology, 2018
    Co-Authors: Xiaoyou Shi, David J Clark, Tian-zhi Guo, Peyman Sahbaie, Kenner C. Rice, Agnieszka Sulima, Wade S. Kingery
    Abstract:

    What we already know about this topic WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: This study tested the hypothesis that ad lib running wheel exercise in a Tibia Fracture model of complex regional pain syndrome can reverse hindlimb nociceptive sensitization and inflammation in mice. Methods Three weeks after Tibia Fracture, the cast was removed and hindlimb von Frey thresholds and unweighting were tested; the mice were then randomized to either ad lib access to a running wheel for 4 weeks or no wheel access. After 4 weeks the behavioral testing was repeated and then skin, sciatic nerve, and spinal cord tissues collected for polymerase chain reaction and enzyme immunoassay measurements of neuropeptide and inflammatory mediator levels. A similar protocol was used in Fracture mice treated with exercise for 4 weeks, and then the running wheel was removed for 2 weeks. Memory and anxiety were measured in both groups with use of open-field, zero-maze, and novel-objects recognition assays. Results At 7 weeks postFracture the mice with no wheel access exhibited hindlimb allodynia and unweighting, anxiety, memory loss, upregulated spinal neuropeptide signaling, and increased hind paw and spinal inflammatory mediator expression, but the postFracture mice allowed to exercise for 4 weeks exhibited none of these changes (n = 12/cohort). When exercise was stopped for 2 weeks after 4 weeks of running, hindlimb allodynia and unweighting were rekindled, and this nociceptive sensitization was associated with increased sciatic nerve neuropeptide levels and hind paw skin interleukin 6 and nerve growth factor expression (n = 12/cohort). Conclusions Daily exercise reversed nociceptive sensitization, inflammation, anxiety, and memory loss after Tibia Fracture.

  • Neuropeptide regulation of adaptive immunity in the Tibia Fracture model of complex regional pain syndrome
    Journal of neuroinflammation, 2018
    Co-Authors: Tian-zhi Guo, Frank Birklein, Tanja Schlereth, Wade S. Kingery, Xiaoyou Shi, J. David Clark
    Abstract:

    Both dysfunctional neuropeptide signaling and immune system activation are characteristic of complex regional pain syndrome (CRPS). Unknown is whether substance P (SP) or calcitonin gene-related peptide (CGRP) support autoantibody production and, consequently, nociceptive sensitization. These experiments involved the use of a well-characterized Tibia Fracture model of CRPS. Mice deficient in SP expression (Tac1−/−) and CGRP signaling (RAMP1−/−) were used to probe the neuropeptide dependence of post-Fracture sensitization and antibody production. The deposition of IgM in the spinal cord, sciatic nerves, and skin was followed using Western blotting, as was expression of the CRPS-related autoantigen cytokeratin 16 (Krt16). Passive serum transfer to B-cell-deficient muMT mice was used to assess the production of functional autoantibodies in CRPS model mice. The use of immunohistochemistry allowed us to assess neuropeptide-containing fiber distribution and Langerhans cell abundance in mouse and human CRPS patient skin, while Langerhans cell-deficient mice were used to assess the functional contributions of these cells. Functional SP and CGRP signaling were required both for the full development of nociceptive sensitization after Fracture and the deposition of IgM in skin and neural tissues. Furthermore, the passive transfer of serum from wildtype but not neuropeptide-deficient mice to Fractured muMT mice caused enhanced allodynia and postural unweighting. Langerhans cells were increased in number in the skin of Fracture mice and CRPS patients, and those increases in mice were reduced in neuropeptide signaling-deficient animals. Unexpectedly, Langerhans cell-deficient mice showed normal nociceptive sensitization after Fracture. However, the increased expression of Krt16 after Tibia Fracture was not seen in neuropeptide-deficient mice. Collectively, these data support the hypothesis that neuropeptide signaling in the Fracture limb of mice is required for autoantigenic IgM production and nociceptive sensitization. The mechanism may be related to neuropeptide-supported autoantigen expression.

Tzuping Wei - One of the best experts on this subject based on the ideXlab platform.

  • complex regional pain syndrome patient immunoglobulin m has pronociceptive effects in the skin and spinal cord of Tibia Fracture mice
    Pain, 2020
    Co-Authors: Tian-zhi Guo, David J Clark, Frank Birklein, Tzuping Wei, Maral Tajerian, Andreas Goebel, Peyman Sahbaie, Fabiola L Escolano, Myriam Herrnberger
    Abstract:

    It has been proposed that complex regional pain syndrome (CRPS) is a post-traumatic autoimmune disease. Previously, we observed that B cells are required for the full expression of CRPS-like changes in a mouse Tibia Fracture model and that serum immunoglobulin M (IgM) antibodies from Fracture mice have pronociceptive effects in muMT Fracture mice lacking B cells. The current study evaluated the pronociceptive effects of injecting CRPS patient serum or antibodies into muMT Fracture mice by measuring hind paw allodynia and unweighting changes. Complex regional pain syndrome serum binding was measured against autoantigens previously identified in the Fracture mouse model. Both CRPS patient serum or IgM antibodies had pronociceptive effects in the Fracture limb when injected systemically in muMT Fracture mice, but normal subject serum and CRPS patient IgG antibodies had no effect. Furthermore, CRPS serum IgM antibodies had pronociceptive effects when injected into the Fracture limb hind paw skin or intrathecally in the muMT Fracture mice. Early (1-12 months after injury) CRPS patient (n = 20) sera were always pronociceptive after systemic injection, and chronic (>12 months after injury) CRPS sera were rarely pronociceptive (2/20 patients), while sera from normal subjects (n = 20) and from patients with uncomplicated recoveries from orthopedic surgery and/or Fracture (n = 15) were never pronociceptive. Increased CRPS serum IgM binding was observed for keratin 16, histone 3.2, gamma actin, and alpha enolase autoantigens. We postulate that CRPS patient IgM antibodies bind to neoantigens in the Fracture mouse skin and spinal cord to initiate a regionally restricted pronociceptive complement response potentially contributing to the CRPS disease process.

  • sex differences in the temporal development of pronociceptive immune responses in the Tibia Fracture mouse model
    Pain, 2019
    Co-Authors: Tian-zhi Guo, David J Clark, Xiaoyou Shi, Tzuping Wei, Wade S. Kingery
    Abstract:

    Previously, distinct sex differences were observed in the pronociceptive role of spinal immune cells in neuropathic and inflammatory mouse pain models. Both peripheral and central innate and adaptive immune changes contribute to sensitization in the Tibia Fracture rodent model of complex regional pain syndrome, and the current study evaluated sex differences in the development of pronociceptive immune responses after Fracture. At 4 and 7 weeks after Fracture, the analgesic effects of a microglia inhibitor were tested in male and female mice, and polymerase chain reaction was used to measure inflammatory mediator expression in skin and spinal cord. The temporal progression of complex regional pain syndrome-like changes in male and female wild-type and muMT Fracture mice lacking B cells and antibodies were evaluated, and IgM antibody deposition measured. Pronociceptive effects of injecting wild-type Fracture mouse serum into muMT Fracture mice were also tested in both sexes, and the role of sex hormones was evaluated in the postFracture development of pronociceptive immune responses. Long-lasting immune changes developed in the Fracture limb and corresponding spinal cord of both male and female mice, including upregulated neuropeptide and cytokine signaling, microglial activation, and pronociceptive autoimmunity. These complex postFracture immune responses were sexually dichotomous and interacted in temporally evolving patterns that generated post-traumatic nociceptive sensitization in both sexes lasting for up to 5 months. Unfortunately, the redundancy and plasticity of these chronic post-traumatic immune responses suggest that clinical interventions focusing on any single specific pronociceptive immune change are likely to be ineffectual.

  • bisphosphonates inhibit pain bone loss and inflammation in a rat Tibia Fracture model of complex regional pain syndrome
    Anesthesia & Analgesia, 2016
    Co-Authors: Liping Wang, Tian-zhi Guo, Xiaoyou Shi, Tzuping Wei, Jillian M R Clark, Wade S. Kingery
    Abstract:

    BACKGROUND:Bisphosphonates are used to prevent the bone loss and Fractures associated with osteoporosis, bone metastases, multiple myeloma, and osteogenesis deformans. Distal limb Fractures cause regional bone loss with cutaneous inflammation and pain in the injured limb that can develop into comple

  • substance p spinal signaling induces glial activation and nociceptive sensitization after Fracture
    Neuroscience, 2015
    Co-Authors: Tian-zhi Guo, David J Clark, Xiaoyou Shi, Tzuping Wei, Yuan Sun, Wade S. Kingery
    Abstract:

    Tibia Fracture in rodents induces substance P (SP)-dependent keratinocyte activation and inflammatory changes in the hindlimb, similar to those seen in complex regional pain syndrome (CRPS). In animal pain models spinal glial cell activation results in nociceptive sensitization. This study tested the hypothesis that limb Fracture triggers afferent C-fiber SP release in the dorsal horn, resulting in chronic glial activation and central sensitization. At 4 weeks after Tibia Fracture and casting in rats, the cast was removed and hind paw allodynia, unweighting, warmth, and edema were measured, then the antinociceptive effects of microglia (minocycline) or astrocyte (L-2-aminoadipic acid (LAA)) inhibitors or an SP receptor antagonist (LY303870) were tested. Immunohistochemistry and PCR were used to evaluate microglial and astrocyte activation in the dorsal horn. Similar experiments were performed in intact rats after brief sciatic nerve electric stimulation at C-fiber intensity. Microglia and astrocytes were chronically activated at 4 weeks after Fracture and contributed to the maintenance of hind paw allodynia and unweighting. Furthermore, LY303870 treatment initiated at 4 weeks after Fracture partially reversed both spinal glial activation and nociceptive sensitization. Similarly, persistent spinal microglial activation and hind paw nociceptive sensitization were observed at 48 h after sciatic nerve C-fiber stimulation and this effect was inhibited by treatment with minocycline, LAA, or LY303870. These data support the hypothesis that C-fiber afferent SP signaling chronically supports spinal neuroglial activation after limb Fracture and that glial activation contributes to the maintenance of central nociceptive sensitization in CRPS. Treatments inhibiting glial activation and spinal inflammation may be therapeutic for CRPS.

  • facilitated spinal neuropeptide signaling and upregulated inflammatory mediator expression contribute to postFracture nociceptive sensitization
    Pain, 2015
    Co-Authors: Xiaoyou Shi, Tian-zhi Guo, Tzuping Wei, David M Clark, Wade S. Kingery
    Abstract:

    Tibia Fracture induces exaggerated substance P (SP) and calcitonin gene-related peptide (CGRP) signaling and neuropeptide-dependent nociceptive and inflammatory changes in the hind limbs of rats similar to those seen in complex regional pain syndrome. Inflammatory changes in the spinal cord contribute to nociceptive sensitization in a variety of animal pain models. This study tested the hypothesis that Fracture-induced exaggerated neuropeptide signaling upregulates spinal inflammatory mediator expression, leading to postFracture hind limb nociceptive sensitization. At 4 weeks after performing Tibia Fracture and casting in rats, we measured hind limb allodynia, unweighting, warmth, edema, and spinal cord neuropeptide and inflammatory mediator content. The antinociceptive effects of intrathecally injected neuropeptide and inflammatory mediator receptor antagonists were evaluated in Fracture rats. Transgenic Fracture mice lacking SP or the CGRP RAMP1 receptor were used to determine the effects of neuropeptide signaling on postFracture pain behavior and spinal inflammatory mediator expression. Hind limb allodynia, unweighting, warmth, edema, increased spinal SP and CGRP, and increased spinal inflammatory mediator expression (TNF, IL-1, IL-6, CCL2, and nerve growth factor) were observed at 4 weeks after Fracture in rats. Fracture-induced increases in spinal inflammatory mediators were not observed in Fracture mice lacking SP or the CGRP receptor, and these mice had attenuated postFracture nociceptive sensitization. Intrathecal injection of selective receptor antagonists for SP, CGRP, TNF, IL-1, IL-6, CCL2, or nerve growth factor each reduced pain behaviors in the Fracture rats. Collectively, these data support the hypothesis that facilitated spinal neuropeptide signaling upregulates the expression of spinal inflammatory mediators contributing to nociceptive sensitization in a rodent Fracture model of complex regional pain syndrome.