Therapeutic and prophylactic effects of macrophage-derived small extracellular vesicles in the attenuation of inflammatory pain.
Therapeutic and prophylactic effects of macrophage-derived small extracellular vesicles in the attenuation of inflammatory pain.
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DOI：
10.1016/j.bbi.2021.02.005
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Ajit SK
中科院分区：
文献类型：
--
作者：
Jean-Toussaint R;Lin Z;Tian Y;Gupta R;Pande R;Luo X;Hu H;Sacan A;Ajit SK
来源于抗原呈递细胞如巨噬细胞的小细胞外囊泡（sEV）可以诱导治疗相关的免疫应答。在脂多糖（LPS）刺激后，抗炎miRNA在RAW 264.7小鼠巨噬细胞分泌的sEV中升高。我们观察到这些sEV被原代小鼠皮质神经元、小胶质细胞和星形胶质细胞摄取，随后在受体细胞中下调促炎性miRNA靶基因。用这些sEV预处理原发性小胶质细胞降低了促炎基因表达。单次鞘内注射源自LPS刺激的RAW 264.7细胞的sEV减弱了炎性疼痛和福尔马林诱导的急性疼痛的完全弗氏佐剂（CFA）小鼠模型中的机械性痛觉过敏。重要的是，sEV没有改变对照小鼠的正常疼痛阈值。脊髓背角的RNA测序显示sEV诱导的免疫调节途径的调节。此外，两周前单次预防性鞘内注射sEV减弱了CFA诱导的疼痛超敏反应，并且在福尔马林模型中无效。这表明预防性sEV施用可以有益于减轻慢性疼痛而不影响对保护性生理和急性炎性疼痛的反应。sEV的预防性给药可以为慢性疼痛的安全和新型疫苗样治疗奠定基础，或作为佐剂，可能减少缓解疼痛所需的药物剂量。
Small extracellular vesicles (sEVs) derived from antigen-presenting cells such as macrophages can induce therapeutically relevant immune responses. Anti-inflammatory miRNAs are elevated in sEVs secreted by RAW 264.7 mouse macrophages after lipopolysaccharide (LPS) stimulation. We observed uptake of these sEVs by primary mouse cortical neurons, microglia and astrocytes followed by downregulation of proinflammatory miRNA target genes in recipient cells. Pre-treating primary microglia with these sEVs decreased pro-inflammatory gene expression. A single intrathecal injection of sEVs derived from LPS stimulated RAW 264.7 cells attenuated mechanical hyperalgesia in the complete Freund’s adjuvant (CFA) mouse model of inflammatory pain and formalin induced acute pain. Importantly, sEVs did not alter the normal pain threshold in control mice. RNA sequencing of dorsal horn of the spinal cord showed sEVs-induced modulation of immune regulatory pathways. Further, a single prophylactic intrathecal injection of sEVs two weeks prior, attenuated CFA-induced pain hypersensitivity and was ineffective in formalin model. This indicates that prophylactic sEVs administration can be beneficial in attenuating chronic pain without impacting responses to the protective physiological and acute inflammatory pain. Prophylactic administration of sEVs could form the basis for a safe and novel vaccine-like therapy for chronic pain or as an adjuvant, potentially reducing the dose of drugs needed for pain relief.
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DOI：
10.4049/jimmunol.1101235
发表时间：
2011-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lu TX;Hartner J;Lim EJ;Fabry V;Mingler MK;Cole ET;Orkin SH;Aronow BJ;Rothenberg ME
通讯作者：
Rothenberg ME
DOI：
10.1093/rheumatology/kex308
发表时间：
2018-03-01
期刊：
Rheumatology (Oxford, England)
影响因子：
--
作者：
Raoof R;Willemen HLDM;Eijkelkamp N
通讯作者：
Eijkelkamp N
影响因子：
16.6
作者：
Pratama, Alvin;Srivastava, Monika;Williams, Naomi J.;Papa, Ilenia;Lee, Sau K.;Dinh, Xuyen T.;Hutloff, Andreas;Jordan, Margaret A.;Zhao, Jimmy L.;Casellas, Rafael;Athanasopoulos, Vicki;Vinuesa, Carola G.
通讯作者：
Vinuesa, Carola G.
影响因子：
14.8
作者：
Huang, Da Wei;Sherman, Brad T.;Lempicki, Richard A.
通讯作者：
Lempicki, Richard A.
影响因子：
120.1
作者：
EL Andaloussi, Samir;Maeger, Imre;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.