Xie Longlong, Deng Xiangying, Li Xiao, Li Xun, Wang Xiangyu, Yan Haipeng, Zhao Lin, Yang Dan, Luo Ting, Yang Yufan, Xiao Zhenghui, Lu Xiulan
Department of Radiology, Hunan Provincial Key Laboratory of Pediatric Orthopedics, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan children's hospital), Changsha, Hunan, China.
Department of Pediatric Intensive Care Unit (PICU) and Hunan Provincial Key Laboratory of Emergency Medicine for Children, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan children's hospital), Changsha, Hunan, China.
Cell Death Discov. 2024 Oct 9;10(1):431. doi: 10.1038/s41420-024-02202-0.
Persistent macrophage activation and cytokine storms are critical causes for the rapid disease progression and high mortality rate of Secondary Hemophagocytic lymphohistiocytosis (sHLH). Identification of key regulatory factors that govern the activation of macrophages is vital. Plasma exosomal circular RNAs (circRNAs) are considered important biomarkers and potential therapeutic targets for various diseases, however, their function in sHLH is still unclear. In this study, we demonstrated for the first time that circMETTL3, derived from METTL3, is upregulated in sHLH patient plasma exosomes, which may plays an important role in the diagnosis of sHLH. Significantly, we also revealed that a novel peptide encoded by circMETTL3, METTL3-156aa, is an inducer of M1 macrophage polarization, which is responsible for the development of cytokine storms during sHLH. We then identified that METTL3-156aa binding with lactate dehydrogenase A (LDHA) and promotes M1 macrophage polarization by enhancing macrophage glycolysis. Additionally, the glycolysis metabolite lactate upregulates the cleavage factor SRSF10 expression by lactylation. This results in increased splicing of the pre-METTL3 mRNA, leading to an enchance in the production of cirMETTL3. Therefore, our results suggest that the circMETTL3/METTL3-156aa/LDHA/Lactate/SRSF10 axis forms a positive feedback loop and may be a novel therapeutic target for the treatment of sHLH.
持续性巨噬细胞活化和细胞因子风暴是继发性噬血细胞性淋巴组织细胞增生症（sHLH）疾病快速进展和高死亡率的关键原因。识别调控巨噬细胞活化的关键调节因子至关重要。血浆外泌体环状RNA（circRNAs）被认为是各种疾病的重要生物标志物和潜在治疗靶点，然而，它们在sHLH中的作用仍不清楚。在本研究中，我们首次证明，源自METTL3的circMETTL3在sHLH患者血浆外泌体中上调，这可能在sHLH的诊断中起重要作用。重要的是，我们还发现circMETTL3编码的一种新型肽METTL3-156aa是M1巨噬细胞极化的诱导剂，它在sHLH期间细胞因子风暴的发展中起作用。然后我们确定METTL3-156aa与乳酸脱氢酶A（LDHA）结合，并通过增强巨噬细胞糖酵解促进M1巨噬细胞极化。此外，糖酵解代谢产物乳酸通过乳酰化上调切割因子SRSF10的表达。这导致前体METTL3 mRNA的剪接增加，从而导致circMETTL3的产生增加。因此，我们的结果表明circMETTL3/METTL3-156aa/LDHA/乳酸/SRSF10轴形成一个正反馈环，可能是治疗sHLH的一个新的治疗靶点。
