IL-6 signaling mediates the germinal center response, IgM production and nociceptive sensitization in male mice after tibia fracture.
IL-6 signaling mediates the germinal center response, IgM production and nociceptive sensitization in male mice after tibia fracture.
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DOI：
10.1016/j.bbi.2021.02.015
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Clark JD
中科院分区：
文献类型：
--
作者：
Li WW;Yang Y;Guo TZ;Sahbaie P;Shi XY;Guang Q;Kingery WS;Herzenberg LA;Clark JD
上调的白细胞介素6（IL-6）信号传导、免疫系统激活和原伤害感受性自身抗体是复杂性局部疼痛综合征（CRPS）的特征。已知IL-6促进B细胞分化，因此我们假设IL-6信号传导在CRPS小鼠胫骨骨折模型中的适应性免疫应答和伤害性敏化的发展中起关键作用。IL-6表达缺陷（IL-6−/−）或B细胞缺陷（muMT）的小鼠经历胫骨骨折和3周的石膏固定或假损伤。使用Western印迹法追踪骨折肢体中IgM的沉积，并使用被动血清转移至muMT骨折小鼠来检测伤害感受支持自身抗体。评估淋巴结肥大，使用qPCR和ELISA测量IL-6表达，并使用FACS和免疫组织化学评价生发中心形成。还在CRPS骨折模型中评价了外源性中和抗IL-6抗体的治疗效果。功能性IL-6信号传导是骨折后伤害性敏化、血管变化和受伤肢体皮肤中IgM免疫复合物沉积的发展所必需的。将来自野生型而非IL-6−/−骨折小鼠的血清被动转移到muMT骨折小鼠中，导致异常性疼痛和姿势性减重增强。IL-6−/−骨折小鼠在骨折后显示出减少的腘淋巴结病。在野生型小鼠的腘淋巴结中检测到了中枢反应，但在IL-6−/−骨折小鼠中未检测到中枢反应。我们观察到IL-6的表达显着增强，在腘淋巴结组织骨折后。相反地，施用抗IL-6抗体减少骨折后的伤害感受和血管变化，并抑制淋巴结病。总的来说，这些数据支持的假设，IL-6信号在小鼠骨折肢需要生发中心的形成，IgM自身抗体的生产和伤害性敏化。因此，抗IL-6治疗可能会减少肢体骨折后或CRPS背景下的疼痛。
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. 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. 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. 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.
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影响因子：
7.4
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Guo TZ;Shi X;Li WW;Wei T;Clark JD;Kingery WS
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