IL-25调控NK细胞改善肥胖的作用及免疫代谢机制研究

Obesity is a state of systemic chronic inflammation, and proinflammatory (M1) polarization of macrophages has long been recognized as an important factor leading to metabolic inflammation, while the key role of NK cells in metabolic inflammation and homeostasis has only recently gained attention. Recently, it has been found that the number and activation of NK cells are increased in obesity, as well as exhibit a specific IL-6Ra+CSF1R+ inflammatory phenotype, which mediates metabolic inflammation and insulin resistance. We have previously found that IL-25 improves obesity via promoting M2 polarization of macrophages. However, the role of IL-25 on NK cells is not clear, and the role of IL-25 on NK cell numbers, activation and phenotype have not been reported. Pre-experiments show that IL-25 can inhibit the body weight gain and improve insulin resistance in obese mice, reduce the infiltration and activation of NK cells in adipose tissue, and inhibit its differentiation into IL-6Ra+CSF1R+ inflammatory phenotype, suggesting that IL-25 can improve obesity via regulating NK cells. This study is intended to: further clarify whether IL-25 improves obesity by regulating NK cell number, activation and phenotype, and elucidate its molecular mechanism. It aims to clarify important regulatory molecules and regulatory mechanisms in obesity, which provide theoretical basis and novel target for the treatment of obesity.

肥胖是一种全身慢性炎症状态，巨噬细胞的促炎（M1）极化一直被认为是导致代谢炎症的重要因素，而NK细胞在代谢炎症和稳态调节中的关键作用近年来才被重视。最近发现肥胖时NK细胞增多且活化增强，还呈现特殊的IL-6Ra+CSF1R+炎症表型，产生大量炎症因子，介导炎症和胰岛素抵抗，并能诱发巨噬细胞M1极化。我们以往发现IL-25通过促进巨噬细胞向M2型极化改善肥胖，而IL-25对NK细胞的调控作用尚不明确，其对NK细胞数量、活化和表型的影响尚未见报道。预实验显示IL-25可抑制肥胖小鼠的体重增长并改善胰岛素抵抗，减少脂肪组织NK细胞的浸润和活化，并抑制其向IL-6Ra+CSF1R+炎症表型分化，提示IL-25可调控NK细胞改善肥胖。本研究拟：进一步明确IL-25是否通过调控NK细胞数量、活化和表型改善肥胖，并阐明其分子机制。旨在明确肥胖等的重要调控分子及调控机制，为治疗肥胖等提供理论基础和新靶点。

肥胖及其相关疾病已成为一项全球性的健康问题，发生率逐年递增，与糖尿病、心血管疾病、内分泌疾病以及肿瘤等疾病密切相关，严重影响患者的生活质量。肥胖是一种全身慢性炎症状态，NK细胞在代谢炎症和稳态调节中的关键作用近年来才被重视。最近发现肥胖时NK细胞增多且活化增强，还呈现特殊的IL-6Ra+CSF1R+炎症表型，产生大量炎症因子，介导炎症和胰岛素抵抗。我们以往发现IL-25通过促进巨噬细胞向M2型极化改善肥胖，而IL-25对NK细胞的调控作用尚不明确，其对NK细胞数量、活化和表型的影响尚未见报道。本研究表明IL-25可抑制肥胖小鼠的体重增长并改善胰岛素抵抗；减少脂肪组织和肝组织中NK细胞的浸润和活化，并抑制其向IL-6Ra+CSF1R+炎症表型分化，提示IL-25可调控NK细胞改善肥胖；IL-25 可能调控氧化磷酸化、能量产生、代谢调控等相关通路；IL-25可能影响NK细胞中NF-κB和mTOR等信号通路从而调控其活化、功能和表型等。本项目将有助于阐明IL-25在肥胖等代谢性疾病中的关键作用和机制，为防治肥胖等疾病提供新思路和干预靶点。项目执行过程中已发表标注该基金资助的SCI论文2篇；项目培养硕士生2名。