GFAP palmitoylcation mediated by ZDHHC23 in spinal astrocytes contributes to the development of neuropathic pain
GFAP palmitoylcation mediated by ZDHHC23 in spinal astrocytes contributes to the development of neuropathic pain
复制标题
DOI：
10.1136/rapm-2023-104980
复制
发表时间：
2023-11
影响因子：
5.1
通讯作者：
Xiaoqing Fan;Siyu Zhang;Suling Sun;Wenxu Bi;Shuyang Li;Wei Wang;Xueran Chen;Zhiyou Fang
中科院分区：
文献类型：
--
作者：
Xiaoqing Fan;Siyu Zhang;Suling Sun;Wenxu Bi;Shuyang Li;Wei Wang;Xueran Chen;Zhiyou Fang
研究背景癌痛对患者的生活质量有重要影响。星形胶质细胞在癌症疼痛信号中起着重要作用。直接靶向星形胶质细胞可以有效地抑制癌痛，但也会引起许多副作用。因此，迫切需要确定癌症疼痛中星形胶质细胞所涉及的特定信号通路或蛋白作为治疗疼痛的靶点。方法将S肉瘤细胞接种于C57BL/6小鼠右侧坐骨神经周围，建立神经病理性癌痛模型。用von Frey细丝测量自发性持续性疼痛和足爪收缩阈值。以NCP脊髓背角(L4-L6)和小鼠星形胶质细胞系MA-C为研究对象，采用酰基生物素交换、实时聚合酶链式反应、酶联免疫吸附试验、免疫印迹和免疫荧光染色等方法对蛋白质棕榈酰化进行了研究。结果在癌性疼痛模型中，随着肿瘤的生长、周围神经组织的侵袭和癌性疼痛的发生，脊髓背角星形胶质细胞被激活，棕榈酰转移酶ZDHHC23表达上调，导致GFAP的棕榈酰化水平增加，炎性因子如(C-X-C基序)配体(CXCL-10)、白介素6和粒细胞-巨噬细胞集落刺激因子的分泌增加。这些因子又通过激活信号转导和转录激活因子3(STAT3)信号通路来激活星形胶质细胞。设计了一种针对GFAP棕榈酰化的竞争性多肽，以有效减轻癌症疼痛治疗中的吗啡耐受性，以及癌症疼痛信号和炎症因子的分泌。结论在啮齿动物模型中，靶向GFAP棕榈酰化似乎是缓解癌痛和吗啡耐受的有效策略。人类的翻译研究是有必要的。
Background Cancer pain has a significant impact on patient’s quality of life. Astrocytes play an important role in cancer pain signaling. The direct targeting of astrocytes can effectively suppress cancer pain, however, they can cause many side effects. Therefore, there is an urgent need to identify the specific signaling pathways or proteins involved within astrocytes in cancer pain as targets for treating pain. Methods A neuropathic cancer pain (NCP) model was established by inoculating mouse S-180 sarcoma cells around the right sciatic nerve in C57BL/6 mice. Spontaneous persistent pain and paw withdrawal thresholds were measured using von Frey filaments. The NCP spinal cord dorsal horn (L4–L6) and mouse astrocyte cell line MA-C were used to study protein palmitoylation using acyl-biotin exchange, real-time polymerase chain reaction, ELISA, western blotting, and immunofluorescent staining. Results In a cancer pain model, along with tumor growth, peripheral nerve tissue invasion, and cancer pain onset, astrocytes in the dorsal horn of the spinal cord were activated and palmitoyltransferase ZDHHC23 expression was upregulated, leading to increased palmitoylation levels of GFAP and increased secretion of inflammatory factors, such as (C–X–C motif) ligand (CXCL)10 (CXCL-10), interleukin 6, and granulocyte-macrophage colony-stimulating factor. These factors in turn activate astrocytes by activating the signal transducer and activator of transcription 3 (STAT3) signaling pathway. A competitive peptide targeting GFAP palmitoylations was designed to effectively alleviate morphine tolerance in cancer pain treatment as well as cancer pain signaling and inflammatory factor secretion. Conclusions In a rodent model, targeting GFAP palmitoylation appears to be an effective strategy in relieving cancer pain and morphine tolerance. Human translational research is warranted.