Department of Microbiology, Moyne Institute of Preventative Medicine, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland.
APC Microbiome Ireland, University College Cork, Cork, Ireland.
Front Cell Infect Microbiol. 2021 Jul 19;11:622491. doi: 10.3389/fcimb.2021.622491. eCollection 2021.
The metabolite-rich environment that is the intestinal lumen contains metabolic by-products deriving from microbial fermentation and host cell metabolism, with resident macrophages being constantly exposed to this metabolic flux. Succinate, lactate and itaconate are three metabolites secreted by primed macrophages due to a fragmented tri-carboxylic acid (TCA) cycle. Additionally, succinate and lactate are known by-products of microbial fermentation. How these metabolites impact biological functioning of resident macrophages particularly in response to bacterial infection remains poorly understood. We have investigated the potential influence of these metabolites on macrophage phagocytosis and clearance of () infection. Treatment of murine bone-marrow-derived macrophages (BMDMs) with succinate reduced numbers of intracellular early during infection, while lactate-treated BMDMs displayed no difference throughout the course of infection. Treatment of BMDMs with itaconate lead to higher levels of intracellular early in the infection with bacterial burden subsequently reduced at later time-points compared to untreated macrophages, indicative of enhanced engulfment and killing capabilities of macrophages in response to itaconate. Expression of engulfment mediators MARCKS, RhoB, and CDC42 were reduced or unchanged following succinate or lactate treatment and increased in itaconate-treated macrophages following infection. Nitric oxide (NO) levels varied while pro- and anti-inflammatory cytokines differed in secretory levels in all metabolite-treated macrophages post-infection with or in response to lipopolysaccharide (LPS) stimulation. Finally, the basal phenotypic profile of metabolite-treated macrophages was altered according to marker gene expression, describing how fluid macrophage phenotype can be in response to the microenvironment. Collectively, our data suggests that microbe- and host-derived metabolites can drive distinct macrophage functional phenotypes in response to infection, whereby succinate and itaconate regulate phagocytosis and bactericidal mechanisms, limiting the intracellular bacterial niche and impeding the pathogenesis of infection.
富含代谢物的肠道腔环境包含微生物发酵和宿主细胞代谢产生的代谢副产物，驻留巨噬细胞不断暴露于这种代谢流中。琥珀酸、乳酸和衣康酸是被激活的巨噬细胞由于三羧酸（TCA）循环碎片化而分泌的三种代谢物。此外，琥珀酸和乳酸是微生物发酵的已知副产物。这些代谢物如何影响驻留巨噬细胞的生物学功能，特别是对细菌感染的反应，仍知之甚少。我们研究了这些代谢物对巨噬细胞吞噬和清除 () 感染的潜在影响。琥珀酸盐处理的鼠骨髓来源巨噬细胞（BMDM）在感染早期减少了细胞内的数量，而在整个感染过程中，乳酸处理的 BMDM 没有差异。衣康酸盐处理的 BMDM 在感染早期导致细胞内的水平升高，随后在稍后的时间点细菌负荷降低，表明衣康酸盐处理的巨噬细胞吞噬和杀伤能力增强。琥珀酸盐或乳酸处理后吞噬作用介质 MARCKS、RhoB 和 CDC42 的表达减少或不变，而感染后衣康酸盐处理的巨噬细胞表达增加。感染 或脂多糖（LPS）刺激后，所有代谢物处理的巨噬细胞中的一氧化氮（NO）水平不同，促炎和抗炎细胞因子的分泌水平不同。最后，根据标记基因表达改变了代谢物处理的巨噬细胞的基础表型特征，描述了巨噬细胞在何种程度上根据微环境改变其流体表型。总之，我们的数据表明，微生物和宿主来源的代谢物可以在感染时驱动不同的巨噬细胞功能表型，其中琥珀酸和衣康酸调节吞噬作用和杀菌机制，限制细胞内细菌生态位并阻碍感染的发病机制。
