SLAMF8 Downregulates Mouse Macrophage Microbicidal Mechanisms via PI3K Pathways.
SLAMF8 Downregulates Mouse Macrophage Microbicidal Mechanisms via PI3K Pathways.
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DOI：
10.3389/fimmu.2022.910112
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
信号转导的淋巴细胞活化分子家族8(SLAMF8)参与了NADPH氧化酶活性的负性调节。然而，SLAMF8下调对巨噬细胞功能和杀微生物剂机制的影响仍然不清楚。为了深入研究这一点，我们首先分析了野生型和SLAMF8缺陷的巨噬细胞在不同刺激下的NADPH氧化酶激活途径。在这里，我们描述了在SLAMF8缺乏的巨噬细胞中，ERK1/2和p38 MAP激酶的磷酸化增加，以及NADPH氧化酶亚基的磷酸化增加。此外，使用特定的抑制剂，我们观察到特定的PI3K抑制减少了野生型和SLAMF8缺陷的巨噬细胞之间的差异，PMA、LPS或鼠伤寒沙门氏菌感染刺激了它们。因此，SLAMF8缺陷的巨噬细胞也表现出更多的小GTP酶，如Rab5和Rab7，以及p47Phox亚单位对细胞质沙门氏菌的募集，这表明SLAMF8缺陷的巨噬细胞的含沙门氏菌空泡(SCV)进程受到损害。无论在体内还是体外，未加SLAMF8的RAW264.7巨噬细胞的iNOS活性、NO产生和IL-6表达均增强，而过表达SLAMF8的RAW264.7巨噬细胞表现出相反的表型。此外，与野生型巨噬细胞相比，SLAMF8缺失的巨噬细胞在干扰素γ和沙门氏菌刺激下表现出更高的src激酶活性和更低的SHP-1磷酸水平。与体外结果一致，与野生型小鼠相比，SLAMF8缺陷小鼠的沙门氏菌清除量增加。因此，SLAMF8对细菌感染的干预下调了小鼠巨噬细胞的激活，证实了SLAMF8受体有可能成为治疗严重或未缓解炎症的潜在靶点。
Signaling lymphocytic activation molecule family 8 (SLAMF8) is involved in the negative modulation of NADPH oxidase activation. However, the impact of SLAMF8 downregulation on macrophage functionality and the microbicide mechanism remains elusive. To study this in depth, we first analyzed NADPH oxidase activation pathways in wild-type and SLAMF8-deficient macrophages upon different stimulus. Herein, we describe increased phosphorylation of the Erk1/2 and p38 MAP kinases, as well as increased phosphorylation of NADPH oxidase subunits in SLAMF8-deficient macrophages. Furthermore, using specific inhibitors, we observed that specific PI3K inhibition decreased the differences observed between wild-type and SLAMF8-deficient macrophages, stimulated with either PMA, LPS, or Salmonella typhimurium infection. Consequently, SLAMF8-deficient macrophages also showed increased recruitment of small GTPases such as Rab5 and Rab7, and the p47phox subunit to cytoplasmic Salmonella, suggesting an impairment of Salmonella-containing vacuole (SCV) progression in SLAMF8-deficient macrophages. Enhanced iNOS activation, NO production, and IL-6 expression were also observed in the absence of SLAMF8 upon Salmonella infection, either in vivo or in vitro, while overexpression of SLAMF8 in RAW264.7 macrophages showed the opposite phenotype. In addition, SLAMF8-deficient macrophages showed increased activation of Src kinases and reduced SHP-1 phosphate levels upon IFNγ and Salmonella stimuli in comparison to wild-type macrophages. In agreement with in vitro results, Salmonella clearance was augmented in SLAMF8-deficient mice compared to that in wild-type mice. Therefore, in conclusion, SLAMF8 intervention upon bacterial infection downregulates mouse macrophage activation, and confirmed that SLAMF8 receptor could be a potential therapeutic target for the treatment of severe or unresolved inflammatory conditions.
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影响因子：
20.3
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