Luo Shiqi, Wang Qiuyi, Chen Ao, Huang Liang, Liu Yaoqi, Zong Xin, Mao Yuanhui
Department of Urology of The Second Affiliated Hospital of Medicine & Liangzhu Laboratory, College of Animal Sciences, Zhejiang University, Hangzhou, China.
Key Laboratory of Molecular Animal Nutrition, Ministry of Education, Hangzhou, China.
PLoS Biol. 2025 Sep 18;23(9):e3003403. doi: 10.1371/journal.pbio.3003403. eCollection 2025 Sep.
Macrophages require rapid and tightly controlled regulatory mechanisms to respond to environmental disruptions. While transcriptional regulation has been well characterized, the mechanisms underlying translational control in macrophages remain poorly understood. Here, we investigated the dynamics of mRNA translation in mouse macrophages during acute, intermediate, and prolonged LPS exposure. Our results reveal clear phase-specific translational regulation during macrophage polarization, which initially increases the synthesis of inflammatory mediators and cytokines, while simultaneously suppressing the expression of cell cycle-related genes. Mechanistically, we observed pervasive upstream translation in the 5' UTRs of cell cycle-related mRNAs, which contributes to cell cycle arrest during the early phase of inflammatory response. Notably, we identified a unique codon preference toward A/U in the third position of codons in macrophages, which contrasts with the G/C preference commonly observed in other tissues. AU codon preference increases the stability and translation efficiency of cell cycle-related mRNAs, promoting cell cycle restoration after extended LPS exposure. These findings reveal that uORF translation and codon usage bias are critical components of translational regulation during macrophage polarization, highlighting a potential therapeutic intervention for modulating immune activation via macrophage-specific codon optimization.
巨噬细胞需要快速且严格控制的调节机制来应对环境干扰。虽然转录调控已得到充分表征，但巨噬细胞中翻译控制的潜在机制仍知之甚少。在这里，我们研究了小鼠巨噬细胞在急性、中期和长期暴露于脂多糖（LPS）期间mRNA翻译的动态变化。我们的结果揭示了巨噬细胞极化过程中明显的阶段特异性翻译调控，这一调控最初增加了炎症介质和细胞因子的合成，同时抑制了细胞周期相关基因的表达。从机制上讲，我们观察到细胞周期相关mRNA的5'非翻译区（UTR）存在普遍的上游翻译，这有助于在炎症反应早期实现细胞周期停滞。值得注意的是，我们在巨噬细胞中发现密码子第三位对A/U具有独特的密码子偏好，这与其他组织中常见的G/C偏好形成对比。AU密码子偏好增加了细胞周期相关mRNA的稳定性和翻译效率，促进了长时间LPS暴露后细胞周期的恢复。这些发现表明，上游开放阅读框（uORF）翻译和密码子使用偏好是巨噬细胞极化过程中翻译调控的关键组成部分，突出了通过巨噬细胞特异性密码子优化来调节免疫激活的潜在治疗干预措施。
