The lack of PI3Kγ favors M1 macrophage polarization and does not prevent kidney diseases progression
The lack of PI3Kγ favors M1 macrophage polarization and does not prevent kidney diseases progression
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DOI：
10.1016/j.intimp.2018.08.020
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发表时间：
2018-11-01
影响因子：
5.6
通讯作者：
Camara, Niels O. S.
中科院分区：
文献类型：
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作者：
Amano, Mariane T.;Castoldi, Angela;Camara, Niels O. S.
急性肾损伤（AKI）和慢性肾脏疾病（CKD）是全球公共卫生关注的主要问题，其病理生理涉及免疫细胞活化，而巨噬细胞是这两个过程的主要参与者之一。提示代谢途径可能参与巨噬细胞的调节，磷脂酰肌醇-3激酶（PI3K）途径在肾脏缺血再灌注和单侧输尿管梗阻（UUO）中被激活。尽管PI3K抑制主要与抗炎反应相关，但其在肾损伤中的应用结果存在争议，这表明需要进一步的研究。我们的目的是揭示PI3K γ在巨噬细胞极化和肾脏疾病发展中的作用。我们分析了野生型（WT）和PI3K敲除（PI3K KO）动物的骨髓巨噬细胞极化。我们观察到在缺乏PI3K γ的情况下，M1 （CD86、CCR7、iNOS、TNF、CXCL9、CXCL10、IL-12和IL-23）的表达增加，M2 （CD206、Arg-1、FIZZ1和YM1）标志物的表达降低。这种调节伴随着PI3K KO M1细胞中较高水平的炎症细胞因子。PI3K KO小鼠稳态肾脏M1增加，急性和慢性肾脏损伤后，这些小鼠没有观察到保护作用。相反，他们表现出更高的蛋白与肌酐比值和Kim-1表达水平，并增加了小管损伤。总之，我们的研究结果表明，PI3K γ的缺乏有利于M1巨噬细胞极化，提供了一个炎症易发的环境，这并不能阻止肾脏疾病的进展。
Acute kidney injury (AKI) and chronic kidney disease (CKD) are major concerns in worldwide public health, and their pathophysiology involves immune cells activation, being macrophages one of the main players of both processes. It is suggested that metabolic pathways could contribute to macrophage modulation and phosphatidylinositol-3 kinase (PI3K) pathway was shown to be activated in kidneys subjected to ischemia and reperfusion as well as unilateral ureteral obstruction (UUO). Although PI3K inhibition is mostly associated with anti-inflammatory response, its use in kidney injuries has been shown controversial results, which indicates the need for further studies. Our aim was to unveil the role of PI3K gamma in macrophage polarization and in kidney diseases development. We analyzed bone-marrow macrophages polarization from wild-type (WT) and PI3K gamma knockout (PI3K KO) animals. We observed increased expression of M1 (CD86, CCR7, iNOS, TNF, CXCL9, CXCL10, IL-12 and IL-23) and decreased of M2 (CD206, Arg-1, FIZZ1 and YM1) markers in the lack of PI3K gamma. And this modulation was accompanied by higher levels of inflammatory cytokines in PI3K KO M1 cells. PI3K KO mice had increased M1 in steady state kidneys, and no protection was observed in these mice after acute and chronic kidney insults. On the contrary, they presented higher levels of protein-to-creatinine ratio and Kim-1 expression and increased tubular injury. In conclusion, our findings demonstrated that the lack of PI3K gamma favors M1 macrophages polarization providing an inflammatory-prone environment, which does not prevent kidney diseases progression.