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公眾號：chem17
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中文摘要：
長春新堿是許多用于兒童和成人惡性腫瘤的方案的重要組成部分，但它會導致劑量限制性感覺運動神經的病變，目前尚無有效的治療方法。本研究旨在描述在長春新堿誘導的神經的病變的小鼠模型中導致機械異常性疼痛和步態障礙發展的神經炎癥機制，并確定新的治療方法。在這里，我們表明長春新堿誘導的周圍神經的病變是由 NLRP3 炎性小體的激活和隨后從巨噬細胞釋放白細胞介素-1β 驅動的，在缺乏 NLRP3 信號通路成分的敲除小鼠中，機械異常性疼痛和步態障礙顯著減少，或在用 NLRP3 抑制劑 MCC950 治療后。此外，在患者來源的髓母細胞瘤異種造影模型中，用 IL-1 受體拮抗劑阿那白滯素治療可以防止長春新堿誘導的神經的病變的發展，而不會對化療效果或腫瘤進展產生不利影響。這些果詳細說明了導致長春新堿誘導的周圍神經的病變的神經炎癥機制，并表明重新利用阿那白滯素可能是預防長春新堿誘導的周圍神經的病變的有效聯合治療策略。
英文摘要：
Vincristine is an important component of many regimens used for pediatric and adult malignancies, but it causes a dose-limiting sensorimotor neuropathy for which there is no effective treatment. This study aimed to delineate the neuro-inflammatory mechanisms contributing to the development of mechanical allodynia and gait disturbances in a murine model of vincristine-induced neuropathy, as well as to identify novel treatment approaches. Here, we show that vincristine-induced peripheral neuropathy is driven by activation of the NLRP3 inflammasome and subsequent release of interleukin-1β from macrophages, with mechanical allodynia and gait disturbances significantly reduced in knockout mice lacking NLRP3 signaling pathway components, or after treatment with the NLRP3 inhibitor MCC950. Moreover, treatment with the IL-1 receptor antagonist anakinra prevented the development of vincristine-induced neuropathy without adversely affecting chemotherapy efficacy or tumor progression in patient-derived medulloblastoma xenograph models. These results detail the neuro-inflammatory mechanisms leading to vincristine-induced peripheral neuropathy and suggest that repurposing anakinra may be an effective co-treatment strategy to prevent vincristine-induced peripheral neuropathy.
論文信息：
論文題目： AMFR drives allergic asthma development by promoting alveolar macrophage–derived GM-CSF production
期刊名稱：JEM- J Exp Med
時間期卷：(2021) 218 (5): e20201452.
在線時間：2021年3月3日
DOI： doi.org/10.1084/jem.20201452
Liposoma巨噬細胞清除劑氯膦酸鹽脂質體Clodronate Liposomes見刊于JEM：
Liposoma巨噬細胞清除劑氯膦酸鹽脂質體Clodronate Liposomes的材料和方法：
JEM期刊率膦酸鹽脂質體清除巨噬細胞專業論文：巨噬細胞清除解決方案。
長春新堿誘導的周圍神經的病變由經典 NLRP3 激活和 IL-1β 釋放驅動，IL-1β 是巨噬細胞釋放。
Depletion of monocytes/macrophages and granulocytes
For depletion of granulocytes, mice were injected i.p. with 200 µg anti-Ly6G antibody or control antibody (Bio X Cell) 3 d before the first vincristine administration and then together with vincristine (i.p.; 0.5 mg/kg) injection as described previously (Daley et al., 2008; Starobova et al., 2019a). For depletion of monocytes, clodronate liposomes (10 µl/g of a 5-mg/ml solution) or control liposome-encapsulated PBS (Liposoma Research) were injected i.p. 3 d before the first vincristine administration and then together with vincristine (i.p.; 0.5 mg/kg) injection as described previously (Barclay et al., 2007; Old et al., 2014; Starobova et al., 2019a; Van Rooijen and Sanders, 1994). To confirm depletion of monocytes or granulocytes, the spleen or blood were collected after two doses of clodronate or Ly6G and/or 24 h after first vincristine (i.p.; 0.5 mg/kg) injection.
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