The polarization of macrophages is critical to inflammation and tissue repair, with unbalanced macrophage polarization associated with critical dysfunctions of the immune system. Cytochrome P450 1A1 (CYP1A1) is a hydroxylase mainly controlled by the inflammation-limiting aryl hydrocarbon receptor (AhR), which plays a critical role in mycoplasma infection, oxidative stress injury, and cancer. Arginase-1 (Arg-1) is a surrogate for polarized alternative macrophages and is important to the production of nitric oxide (NO) by the modulation of arginine. In the present study, we found CYP1A1 to be upregulated in IL-4-stimulated mouse peritoneal macrophages (PMs) and human peripheral blood monocytes. Using CYP1A1-overexpressing RAW264.7 cells (CYP1A1/RAW) we found that CYP1A1 augmented Arg-1 expression by strengthening the activation of the JAK1/STAT6 signaling pathway in macrophages treated with IL-4. 15(S)-HETE, a metabolite of CYP1A1 hydroxylase, was elevated in IL-4-induced CYP1A1/RAW cells. Further, in macrophages, the loss-of-CYP1A1-hydroxylase activity was associated with reduced IL-4-induced Arg-1 expression due to impaired 15(S)-HETE generation. Of importance, CYP1A1 overexpressing macrophages reduced the inflammation associated with LPS-induced peritonitis. Taken together, these findings identified a novel signaling axis, CYP1A1-15(S)-HETE-JAK1-STAT6, that may be a promising target for the proper maintenance of macrophage polarization and may also be a means by which to treat immune-related disease due to macrophage dysfunction.

中文翻译：

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细胞色素P450 1A1通过靶向JAK1 / STAT6增强Arginase-1表达，从而减少LPS诱导的小鼠腹膜炎。

巨噬细胞的极化对于炎症和组织修复至关重要，而巨噬细胞极化的不平衡与免疫系统的严重功能障碍相关。细胞色素P450 1A1（CYP1A1）是主要受炎症限制芳基烃受体（AhR）控制的羟化酶，在支原体感染，氧化应激损伤和癌症中起关键作用。精氨酸酶-1（Arg-1）是极化的替代性巨噬细胞的替代物，对精氨酸的调节对一氧化氮（NO）的生产很重要。在本研究中，我们发现CYP1A1在IL-4刺激的小鼠腹膜巨噬细胞（PMs）和人外周血单核细胞中被上调。使用CYP1A1过表达RAW264。我们在7个细胞（CYP1A1 / RAW）中发现，CYP1A1通过增强用IL-4处理的巨噬细胞中JAK1 / STAT6信号通路的激活来增强Arg-1表达。在IL-4诱导的CYP1A1 / RAW细胞中，CYP1A1羟化酶的代谢产物15（S）-HETE升高。此外，在巨噬细胞中，由于15（S）-HETE的生成受损，CYP1A1-羟化酶活性的丧失与IL-4诱导的Arg-1表达降低有关。重要的是，CYP1A1过表达的巨噬细胞减少了与LPS诱发的腹膜炎相关的炎症。综上所述，这些发现确定了一个新的信号转导轴CYP1A1-15（S）-HETE-JAK1-STAT6，它可能是正确维持巨噬细胞极化的有希望的靶标，也可能是治疗免疫相关疾病的一种手段。巨噬细胞功能障碍引起的疾病。