The Second Clinical Medical Collage, Zhejiang Chinese Medicine University, Hangzhou, 310053, China.
Department of Critical Care Medicine, Zhejiang Hospital, 1229 Gudun Road, Hangzhou, 310030, China.
BMC Immunol. 2021 Nov 8;22(1):72. doi: 10.1186/s12865-021-00463-3.
Macrophages are involved in the pathophysiology of many diseases as critical cells of the innate immune system. Pyroptosis is a form of macrophage death that induces cytokinesis of phagocytic substances in the macrophages, thereby defending against infection. Dimethyl itaconate (DI) is an analog of itaconic acid with anti-inflammatory effects. However, the effect of dimethyl itaconate on macrophage pyroptosis has not been elucidated clearly. Thus, the present study aimed to analyze the effect of DI treatment on a macrophage pyroptosis model (Lipopolysaccharide, LPS + Adenosine Triphosphate, ATP). The results showed that 0.25 mM DI ameliorated macrophage pyroptosis and downregulated interleukin (IL)-1β expression. Then, real-time quantitative polymerase chain reaction (RT-qPCR) was used to confirm the result of RNA-sequencing of the upregulated oxidative stress-related genes (Gclc and Gss) and downregulated inflammation-related genes (IL-12β and IL-1β). In addition, Gene Ontology (GO) enrichment analysis showed that differential genes were associated with transcript levels and DNA replication. Kyoto encyclopedia of genes and genomes (KEGG) enrichment showed that signaling pathways, such as tumor necrosis factor (TNF), Jak, Toll-like receptor and IL-17, were altered after DI treatment. N-acetyl-L-cysteine (NAC) reversed the DI effect on the LPS + ATP-induced macrophage pyroptosis and upregulated the IL-1β expression. Oxidative stress-related protein Nrf2 is involved in the DI regulation of macrophage pyroptosis. Taken together, these findings suggested that DI alleviates the pyroptosis of macrophages through oxidative stress.
巨噬细胞作为先天免疫系统的关键细胞，参与多种疾病的病理生理过程。细胞焦亡是巨噬细胞死亡的一种形式，它诱导巨噬细胞中吞噬物质的细胞分裂，从而抵御感染。二甲基衣康酸（DI）是衣康酸的一种类似物，具有抗炎作用。然而，二甲基衣康酸对巨噬细胞细胞焦亡的影响尚未阐明。因此，本研究旨在分析 DI 处理对巨噬细胞细胞焦亡模型（脂多糖，LPS+三磷酸腺苷，ATP）的影响。结果表明，0.25 mM DI 改善了巨噬细胞细胞焦亡并下调了白细胞介素（IL）-1β的表达。然后，实时定量聚合酶链反应（RT-qPCR）用于确认 RNA 测序结果中与氧化应激相关基因（Gclc 和 Gss）上调和炎症相关基因（IL-12β和 IL-1β）下调相关的结果。此外，基因本体论（GO）富集分析表明差异基因与转录水平和 DNA 复制相关。京都基因与基因组百科全书（KEGG）富集表明，信号通路如肿瘤坏死因子（TNF）、Jak、Toll 样受体和 IL-17 在 DI 处理后发生改变。N-乙酰-L-半胱氨酸（NAC）逆转了 DI 对 LPS+ATP 诱导的巨噬细胞细胞焦亡的作用，并上调了 IL-1β的表达。氧化应激相关蛋白 Nrf2 参与了 DI 对巨噬细胞细胞焦亡的调节。综上所述，这些发现表明 DI 通过氧化应激缓解巨噬细胞的细胞焦亡。
