Suppression of the hyaluronic acid pathway induces M1 macrophages polarization via STAT1 in glioblastoma.
Suppression of the hyaluronic acid pathway induces M1 macrophages polarization via STAT1 in glioblastoma.
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透明质酸途径的抑制通过成胶质细胞瘤中的STAT1诱导M1巨噬细胞极化。
DOI：
10.1038/s41420-022-00973-y
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发表时间：
2022-04-11
影响因子：
7
通讯作者：
Liu, Huailei
中科院分区：
文献类型：
--
作者：
Yan, Tao;Wang, Kaikai;Li, Jiafeng;Hu, Hong;Yang, He;Cai, Meng;Liu, Ruijie;Li, Honglei;Wang, Ning;Shi, Ying;Hua, Wei;Liu, Huailei
肿瘤免疫抑制微环境是影响肿瘤免疫治疗成功的关键因素，而肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）是肿瘤免疫抑制微环境形成的关键。透明质酸（HA）是胶质母细胞瘤微环境的重要组成部分，但它是否有助于TAM极化和胶质母细胞瘤免疫抑制微环境还不太清楚。我们观察到阻断胶质母细胞瘤HA的合成或阻断HA与巨噬细胞表面受体CD 44的结合可通过上调巨噬细胞中的SIRPα来增加M1巨噬细胞的比例，其机制可能是SIRPα的升高增强了巨噬细胞中STAT 1的磷酸化，抑制了STAT 3的磷酸化。随后，诱导的巨噬细胞可以通过反馈效应抑制胶质母细胞瘤的生长。此外，胆囊炎药物4-甲基伞形酮（4 MU）可通过干扰胶质母细胞瘤HA合成来破坏CD 47/SIRPα轴。这些结果表明，HA在巨噬细胞极化和胶质母细胞瘤细胞与巨噬细胞之间的CD 47/SIRPα信号转导中起重要作用，抑制HA通路可能是胶质母细胞瘤免疫治疗的新途径。
Immunosuppressive tumor microenvironment is a crucial factor that impedes the success of tumor immunotherapy, and tumor-associated macrophages (TAMs) are essential for the formation of tumor immunosuppressive microenvironment. Hyaluronic acid (HA) is highly important brick for glioblastoma microenvironment, but whether it contributes to TAM polarization and glioblastoma immunosuppressive microenvironment is less well known. In our study, we observed that disrupting glioblastoma HA synthesis or blocking HA binding to its receptor CD44 on macrophages increased the proportion of M1 macrophages by upregulating SIRPα in macrophages, the underlying mechanism was elevated SIRPα enhanced STAT1 phosphorylation and suppressed STAT3 phosphorylation in macrophages. Subsequently, the induced macrophages could inhibit glioblastoma growth via a feedback effect. In addition, 4-methylumbelliferone (4MU), a cholecystitis drug, can disrupt the CD47/SIRPα axis by disturbing glioblastoma HA synthesis. Collectively, these findings indicated that HA plays a crucial role in macrophages polarization and CD47/SIRPα signaling between glioblastoma cells and macrophages, and suppressing the HA pathway may be a new immunotherapeutic approach for glioblastoma.
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影响因子：
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