KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages.
KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages.
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DOI：
10.1038/cddis.2016.73
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发表时间：
2016-04-07
影响因子：
9
通讯作者：
Limatola C
中科院分区：
文献类型：
--
作者：
Grimaldi A;D'Alessandro G;Golia MT;Grössinger EM;Di Angelantonio S;Ragozzino D;Santoro A;Esposito V;Wulff H;Catalano M;Limatola C
胶质瘤成功侵入脑实质所采取的策略之一是通过将浸润的小胶质细胞/巨噬细胞（M/MΦ）向抗炎、促肿瘤表型转变而将它们转变为盟友。胶质瘤和浸润的M/MΦ细胞都表达Ca 2+激活的K+通道（KCa3.1），并且抑制胶质瘤细胞的KCa3.1活性减少健康脑实质中的肿瘤浸润。我们想知道KCa3.1抑制是否可以阻止M/MΦ细胞获得促肿瘤表型，从而有助于减少胶质瘤的发展。为此，我们研究了在胶质瘤条件培养基中培养或用IL-4处理的小胶质细胞，以及从胶质瘤荷瘤小鼠和人类胶质瘤活检中急性分离的M/MΦ细胞。在这些不同的条件下，M/MΦ总是向抗炎状态极化，并且通过1-[（2-氯苯基）二苯基甲基]-1H-吡唑（TRAM-34）阻止KCa 3.1活化，我们观察到向促炎、抗肿瘤表型的转变。我们确定FAK和PI 3 K/AKT是参与这种表型转换的分子机制，在KCa 3.1之后依次激活。抗炎M/MΦ具有较高的KCa3.1 mRNA（kcnn 4）表达水平，其通过KCa3.1抑制而降低。与这些发现一致，TRAM-34治疗在体内显著减小了携带神经胶质瘤的小鼠中的肿瘤大小。我们的数据表明，KCa 3.1通道参与胶质瘤微环境对浸润M/MΦ的抑制作用，这表明KCa 3.1通道可能作为胶质瘤治疗靶点。
Among the strategies adopted by glioma to successfully invade the brain parenchyma is turning the infiltrating microglia/macrophages (M/MΦ) into allies, by shifting them toward an anti-inflammatory, pro-tumor phenotype. Both glioma and infiltrating M/MΦ cells express the Ca2+-activated K+ channel (KCa3.1), and the inhibition of KCa3.1 activity on glioma cells reduces tumor infiltration in the healthy brain parenchyma. We wondered whether KCa3.1 inhibition could prevent the acquisition of a pro-tumor phenotype by M/MΦ cells, thus contributing to reduce glioma development. With this aim, we studied microglia cultured in glioma-conditioned medium or treated with IL-4, as well as M/MΦ cells acutely isolated from glioma-bearing mice and from human glioma biopsies. Under these different conditions, M/MΦ were always polarized toward an anti-inflammatory state, and preventing KCa3.1 activation by 1-[(2-Chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), we observed a switch toward a pro-inflammatory, antitumor phenotype. We identified FAK and PI3K/AKT as the molecular mechanisms involved in this phenotype switch, activated in sequence after KCa3.1. Anti-inflammatory M/MΦ have higher expression levels of KCa3.1 mRNA (kcnn4) that are reduced by KCa3.1 inhibition. In line with these findings, TRAM-34 treatment, in vivo, significantly reduced the size of tumors in glioma-bearing mice. Our data indicate that KCa3.1 channels are involved in the inhibitory effects exerted by the glioma microenvironment on infiltrating M/MΦ, suggesting a possible role as therapeutic targets in glioma.