Emerging evidence has demonstrated that long noncoding RNAs (lncRNAs) play critical roles in the epigenetic and transcriptional regulation of mammalian circadian systems. Circadian rhythmicity regulates many aspects of our immune system, and perturbation of the circadian clock can augment the inflammatory response. However, knowledge of the precise functions of lncRNAs in the regulation of immune functions within the circadian system is relatively limited. In this study, differentially expressed lncRNAs induced by Clock knockdown were screened via mRNA/lncRNA microarray and bioinformatic prediction analysis. We identified a Clock-regulated lncRNA, AK028245, which was correlated with the activation of the immune response. The expression levels of AK028245 were decreased in the spleen of immunosuppressed mice and elevated in immune-activated mice treated with lipopolysaccharide (LPS). Further, Clock knockdown decreased the expression of OTUD7B and A20, 2 early immune response factors acting on the NF-κB signaling pathway. Interestingly, inhibition of AK028245 increased their expression, mitigating the effects of Clock knockdown. In addition, inhibition of AK028245 downregulated the expression of tumor necrosis factor–α and interleukin-6 in the late stages of LPS stimulation and the expression of interferon-γ and Cxcl12 in the peak stages. We conclude that this newly identified lncRNA plays a role in the crosstalk between Clock and immune response regulators, likely resulting in a proinflammatory response targeting OTUD7B and A20. The lncRNA AK028245 has revealed a new mechanism of the immune response and provided new targets for the treatment of immune disorders.

新出现的证据表明，长链非编码 RNA (lncRNA) 在哺乳动物昼夜节律系统的表观遗传和转录调控中发挥着关键作用。昼夜节律调节我们免疫系统的许多方面，生物钟的扰动可以增强炎症反应。然而，关于 lncRNA 在昼夜节律系统内调节免疫功能的确切功能的知识相对有限。在本研究中，通过 mRNA/lncRNA 微阵列和生物信息学预测分析筛选了由Clock敲低诱导的差异表达 lncRNA 。我们确定了一个时钟-调节的 lncRNA，AK028245，与免疫反应的激活相关。AK028245 的表达水平在免疫抑制小鼠的脾脏中降低，而在用脂多糖 (LPS) 处理的免疫激活小鼠中则升高。此外，Clock敲低降低了作用于 NF-κB 信号通路的 2 个早期免疫反应因子 OTUD7B 和 A20 的表达。有趣的是，AK028245 的抑制增加了它们的表达，减轻了时钟的影响击倒。此外，抑制AK028245可下调LPS刺激后期肿瘤坏死因子-α和白细胞介素6的表达，以及高峰期干扰素-γ和Cxcl12的表达。我们得出结论，这种新发现的 lncRNA 在时钟和免疫反应调节剂之间的串扰中发挥作用，可能导致针对 OTUD7B 和 A20 的促炎反应。lncRNA AK028245揭示了一种新的免疫反应机制，为免疫疾病的治疗提供了新的靶点。