The NLRP3 inflammasome modulates glycolysis by increasing PFKFB3 in an IL-1β-dependent manner in macrophages
The NLRP3 inflammasome modulates glycolysis by increasing PFKFB3 in an IL-1β-dependent manner in macrophages
复制标题
DOI：
10.1038/s41598-019-40619-1
复制
发表时间：
2019-03-11
影响因子：
4.6
通讯作者：
Lynch, Marina A.
中科院分区：
文献类型：
--
作者：
Finucane, Orla M.;Sugrue, Jamie;Lynch, Marina A.
炎症和代谢在炎性疾病期间错综复杂地联系在一起，其中核苷酸结合结构域样受体家族含Pyrin结构域3（NLRP 3）炎性体（一种先天免疫传感器）的激活是至关重要的。几种因素可以激活NLRP 3炎性体，但NLRP 3炎性体激活和代谢之间的联系的性质仍有待深入研究。本研究调查了NLRP 3炎性体的小分子抑制剂MCC 950是否调节巨噬细胞中脂多糖（LPS）和淀粉样蛋白-β（A β）诱导的代谢表型和炎症特征。LPS + A β诱导IL-1 β分泌，而用MCC 950预处理抑制此分泌。LPS + A β还上调IL-1 β mRNA和TNF α、IL-6和IL-10的上清液浓度，然而这些变化对MCC 950不敏感，证实了MCC 950特异性靶向BMDM中的炎性小体活化。LPS + A β增加了糖酵解和糖酵解酶PFKFB 3，而MCC 950降低了这些作用。这些发现表明，NLRP 3炎性小体激活可能在调节糖酵解中发挥作用。为了进一步研究这一点，评估了IL-1 β对糖酵解的影响。IL-1 β刺激糖酵解和PFKFB 3，模拟LPS + A β的作用，并增加了炎性小体活化影响代谢的证据。这一论点得到了以下发现的支持：LPS + A β诱导的糖酵解和PFKFB 3的变化在来自NLRP 3缺陷和IL-1 R1缺陷小鼠的BMDM中减弱。与PFKFB 3的关键作用一致的是发现PFKFB 3抑制剂3 PO减弱LPS + A β诱导的糖酵解。数据表明，NLRP 3炎性体的激活和随后IL-1 β的释放在通过PFKFB 3调节糖酵解中起关键作用。通过靶向NLRP 3炎性小体-PFKFB 3轴恢复代谢稳态可以为治疗急性和慢性疾病提供新的治疗靶点。
Inflammation and metabolism are intricately linked during inflammatory diseases in which activation of the nucleotide-binding domain-like receptors Family Pyrin Domain Containing 3 (NLRP3) inflammasome, an innate immune sensor, is critical. Several factors can activate the NLRP3 inflammasome, but the nature of the link between NLRP3 inflammasome activation and metabolism remains to be thoroughly explored. This study investigates whether the small molecule inhibitor of the NLRP3 inflammasome, MCC950, modulates the lipopolysaccharide (LPS) -and amyloid-beta (A beta)-induced metabolic phenotype and inflammatory signature in macrophages. LPS + A beta induced IL-1 beta secretion, while pre-treatment with MCC950 inhibited this. LPS + A beta also upregulated IL-1 beta mRNA and supernatant concentrations of TNF alpha, IL-6 and IL-10, however these changes were insensitive to MCC950, confirming that MCC950 specifically targets inflammasome activation in BMDMs. LPS + A beta increased glycolysis and the glycolytic enzyme, PFKFB3, and these effects were decreased by MCC950. These findings suggest that NLRP3 inflammasome activation may play a role in modulating glycolysis. To investigate this further, the effect of IL-1 beta on glycolysis was assessed. IL-1 beta stimulated glycolysis and PFKFB3, mimicking the effect of LPS + A beta and adding to the evidence that inflammasome activation impacts on metabolism. This contention was supported by the finding that the LPS + A beta-induced changes in glycolysis and PFKFB3 were attenuated in BMDMs from NLRP3-deficient and IL-1R1-deficient mice. Consistent with a key role for PFKFB3 is the finding that the PFKFB3 inhibitor, 3PO, attenuated the LPS + A beta-induced glycolysis. The data demonstrate that activation of the NLRP3 inflammasome, and the subsequent release of IL-1 beta, play a key role in modulating glycolysis via PFKFB3. Reinstating metabolic homeostasis by targeting the NLRP3 inflammasome-PFKFB3 axis may provide a novel therapeutic target for treatment of acute and chronic disease.