Adenylate kinase 4 is critical to the function of classically activated macrophage

S. Miaw, W. Chin
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Abstract

Macrophage plays a crucial role in the front line of host defense against pathogens. Classically activated macrophages (M1), induced by IFN-g and LPS, highly express inflammatory cytokines and contribute to inflammatory processes. By contrast, alternatively activated macrophages (M2) are induced by IL-4/IL-13, produce IL-10, and display anti-inflammatory activity. Adenylate kinase 4 (Ak4), an enzyme that transfers phosphate group among ATP/GTP, AMP, and ADP, is a key modulator of ATP. Ak4 is involved in maintaining the homeostasis of cellular nucleotides which is essential for cellular function. We observed Ak4 is preferentially expressed in M1 macrophages compared to M2 macrophages. Whether Ak4 is critical for M1 macrophage function remains elusive. Here we demonstrated that Ak4 maintained ATP homeostasis, and was critical for ROS production, glycolysis, and bactericidal ability in M1 macrophages. Moreover, Ak4 promoted the expression of inflammatory genes, including Il1b, Il6, Tnfa, Nos2, Nox2and Hif1a, in M1 macrophages via Hif1a and AMPK. However, Ak4 deficiency did not affect the development of murine immune cells. Taken together, our data depict a potential mechanism linking nucleotide homeostasis and the function of M1 macrophage. Taiwan Ministry of Science and Technology (111-2320-B-002-068-MY3)
腺苷酸激酶4对经典活化巨噬细胞的功能至关重要
巨噬细胞在宿主防御病原体的第一线起着至关重要的作用。经典活化的巨噬细胞(M1),由IFN-g和LPS诱导,高度表达炎症细胞因子并参与炎症过程。相反,交替活化的巨噬细胞(M2)被IL-4/IL-13诱导,产生IL-10,并表现出抗炎活性。腺苷酸激酶4 (Ak4)是ATP/GTP、AMP和ADP之间转移磷酸基的酶,是ATP的关键调节剂。Ak4参与维持细胞核苷酸的稳态,这对细胞功能至关重要。我们观察到与M2巨噬细胞相比,Ak4在M1巨噬细胞中优先表达。Ak4是否对M1巨噬细胞功能至关重要尚不清楚。在这里,我们证明Ak4维持ATP稳态,对M1巨噬细胞的ROS生成、糖酵解和杀菌能力至关重要。此外,Ak4通过Hif1a和AMPK促进M1巨噬细胞中炎性基因Il1b、Il6、Tnfa、Nos2、nox2和Hif1a的表达。然而,Ak4缺乏并不影响小鼠免疫细胞的发育。综上所述,我们的数据描述了一种连接核苷酸稳态和M1巨噬细胞功能的潜在机制。台湾科学技术部(111-2320-B-002-068-MY3)
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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