Progranulin deficiency in Iba-1(+) myeloid cells exacerbates choroidal neovascularization by perturbation of lysosomal function and abnormal inflammation.
Progranulin deficiency in Iba-1(+) myeloid cells exacerbates choroidal neovascularization by perturbation of lysosomal function and abnormal inflammation.
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DOI：
10.1186/s12974-021-02203-1
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发表时间：
2021-07-25
影响因子：
9.3
通讯作者：
Hara H
中科院分区：
文献类型：
--
作者：
Takahashi K;Nakamura S;Otsu W;Shimazawa M;Hara H
视网膜相关性黄斑变性（AMD）是全世界老年人永久失明的主要原因。视网膜下腔的慢性炎症与渗出性AMD的进展相关。颗粒蛋白原（PGRN）是一种由骨髓细胞分泌的生长因子，在控制溶酶体功能中起重要作用。PGRN的缺乏导致中枢神经系统中神经元的炎症。本研究的目的是研究PGRN在激光诱导的脉络膜新生血管（CNV）小鼠中的作用。通过视网膜的激光光凝在C57 BL/6 J小鼠中诱导CNV。测定CNV位点周围PGRN的表达和Iba-1+细胞的积聚。还研究了具有激光诱导的CNVs的Grn−/−、Grn+/−和Grn+/+小鼠。为了评估巨噬细胞对炎症的影响，我们使用了一种巨噬细胞系（RAW264.7），其中PGRN的表达被RNA干扰和来自Grn-/-和Grn+/+小鼠的腹腔巨噬细胞敲低。将这些细胞在缺氧条件（1%O2）下孵育。Iba-1+骨髓细胞迁移并聚集在光凝诱导的CNV区域，并且Grn+/+小鼠的CNV病变分泌高水平的PGRN。在Grn−/−小鼠中CNVs的大小大于Grn+/−和Grn+/+小鼠。在Grn−/−小鼠中，CNV周围眼部浸润的Iba-1+细胞数量更高，这些细胞产生的VEGF-A比Grn+/+小鼠中的细胞更多。RAW264.7细胞的PGRN沉默导致细胞的异常活化。此外，缺氧条件下促进生产的促血管生成和促炎细胞因子从PGRN缺陷的巨噬细胞。有趣的是，溶酶体相关蛋白的表达水平和活化的溶酶体数量在PGRN缺陷的巨噬细胞中增加。这些发现表明Iba-1+细胞中PGRN缺乏激活溶酶体功能，然后导致异常炎症。Iba-1+髓样细胞的异常活化可能参与CNV的进展，调节这些细胞可能是渗出型AMD的新的治疗靶点。在线版本包含补充材料，可通过10.1186/s12974-021-02203-1获得。
Age-related macular degeneration (AMD) is the principal cause of permanent blindness among elderly individuals worldwide. Chronic inflammation in the subretinal space is associated with a progression of exudative AMD. Progranulin (PGRN) is a growth factor secreted from myeloid cells and plays an important role in controlling the lysosomal function. A deficiency in PGRN leads to inflammation of the neurons in the central nervous system. The purpose of this study was to investigate the role played by PGRN in the size of the choroidal neovascularization (CNV) in laser-induced CNV mice. CNVs were induced in C57BL/6J mice by laser photocoagulation of the retina. The expression of PGRN and the accumulation of Iba-1+ cells around the sites of the CNVs were determined. Grn−/−, Grn+/−, and Grn+/+ mice with laser-induced CNVs were also studied. To evaluate the effect of macrophages on the inflammation, we used a macrophage cell line (RAW264.7) in which the expression of PGRN was knocked down by RNA interference and peritoneal macrophages derived from Grn−/− and Grn+/+ mice. These cells were incubated under hypoxic conditions (1% O2). Iba-1+ myeloid cells migrated and accumulated in the photocoagulation-induced CNV areas, and the CNV lesions secreted high levels of PGRN in Grn+/+ mice. The size of the CNVs was larger in Grn−/− mice than in Grn+/− and Grn+/+ mice. In Grn−/− mice, the number of ocular-infiltrating Iba-1+ cells around the CNV was higher, and these cells produced more VEGF-A than the cells in the Grn+/+ mice. PGRN-silencing of RAW264.7 cells led to abnormal activation of the cells. In addition, hypoxic conditions promoted the production of proangiogenic and proinflammatory cytokines from PGRN-deficient macrophages. Interestingly, the expression level of lysosome-associated proteins and the number of activated lysosomes increased in PGRN-deficient macrophages. These findings indicate that PGRN deficiency in Iba-1+ cells activates the lysosomal function that then leads to abnormal inflammation. The aberrant activation of Iba-1+ myeloid cells might contribute to the progression of the CNV and the regulation of these cells might be a novel therapeutic target for exudative AMD. The online version contains supplementary material available at 10.1186/s12974-021-02203-1.
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影响因子：
4
作者：
Bateman, Andrew;Bennett, Hugh P. J.
通讯作者：
Bennett, Hugh P. J.
影响因子：
82.9
作者：
He, ZH;Ong, CHP;Bateman, A
通讯作者：
Bateman, A
DOI：
10.1038/nrn.2017.36
发表时间：
2017-06
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Kao AW;McKay A;Singh PP;Brunet A;Huang EJ
通讯作者：
Huang EJ
影响因子：
4.6
作者：
Cerezo LA;Kuklová M;Hulejová H;Vernerová Z;Kaspříková N;Veigl D;Pavelka K;Vencovský J;Šenolt L
通讯作者：
Šenolt L
影响因子：
16.2
作者：
Hu, Fenghua;Padukkavidana, Thihan;Vaegter, Christian B.;Brady, Owen A.;Zheng, Yanqiu;Mackenzie, Ian R.;Feldman, Howard H.;Nykjaer, Anders;Strittmatter, Stephen M.
通讯作者：
Strittmatter, Stephen M.