Itaconate and fumarate derivatives inhibit priming and activation of the canonical NLRP3 inflammasome in macrophages.
Itaconate and fumarate derivatives inhibit priming and activation of the canonical NLRP3 inflammasome in macrophages.
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NLRP3炎性体是一种多蛋白复合物，可调节caspase-1活化以及随后的白细胞介素（IL）-1 β和IL-18在感染或损伤时从先天免疫细胞释放。代谢产物衣康酸酯和富马酸酯的衍生物、衣康酸二甲酯（DMF）、衣康酸4-辛酯（4OI）和富马酸二甲酯（DMF）限制了NLRP 3炎性小体激活后IL-1 β的表达和释放。然而，这些代谢物衍生物对NLRP 3炎性体反应的直接影响需要进一步研究。使用小鼠骨髓源性巨噬细胞、混合神经胶质细胞和器官型海马切片培养物（OHSC），我们证明了NH4、4OI和DMF预处理抑制响应于脂多糖（LPS）的促炎性细胞因子产生，以及抑制尼日利亚菌素诱导的随后的NLRP 3炎性体激活。在LPS致敏的巨噬细胞、混合神经胶质细胞、OHSC和人巨噬细胞中，4OI、DMF和另一种富马酸酯衍生物富马酸单甲酯（MMF）也直接抑制NLRP 3活化的生化标志物，包括ASC斑点形成、半胱天冬酶-1活化、gasdermin D裂解和IL-1 β释放。DMF（一种获批的多发性硬化症治疗药物）以及地塞米松、4OI和MMF可抑制巨噬细胞中对溶血磷脂酰胆碱（用于诱导脱髓鞘）的NLRP 3活化，表明DMF通过NLRP 3抑制治疗多发性硬化症的可能机制。这些衍生物还减少了对钙离子载体离子霉素的响应的pro-IL-1 α裂解。总之，这些发现揭示了巨噬细胞中NLRP 3激活的引发和激活步骤的免疫代谢调节。此外，我们强调衣康酸盐和富马酸盐衍生物作为NLRP 3和IL-1 α驱动的疾病（包括大脑）的潜在治疗选择。研究了衣康酸酯和富马酸酯衍生物对巨噬细胞和小胶质细胞中典型NLRP 3炎性小体活化的影响。衣康酸盐和富马酸盐衍生物抑制了尼日利亚菌素、咪喹莫特和溶血磷脂酰胆碱刺激后典型NLRP 3激活的启动和激活步骤。这些衍生物还减少了响应于离子霉素的白细胞介素-1 α裂解。
The NLRP3 inflammasome is a multiprotein complex that regulates caspase‐1 activation and subsequent interleukin (IL)‐1β and IL‐18 release from innate immune cells in response to infection or injury. Derivatives of the metabolites itaconate and fumarate, dimethyl itaconate (DMI), 4‐octyl itaconate (4OI) and dimethyl fumarate (DMF) limit both expression and release of IL‐1β following NLRP3 inflammasome activation. However, the direct effects of these metabolite derivatives on NLRP3 inflammasome responses require further investigation. Using murine bone marrow‐derived macrophages, mixed glia and organotypic hippocampal slice cultures (OHSCs), we demonstrate that DMI, 4OI and DMF pretreatments inhibit pro‐inflammatory cytokine production in response to lipopolysaccharide (LPS), as well as inhibit subsequent NLRP3 inflammasome activation induced by nigericin. DMI, 4OI, DMF and monomethyl fumarate (MMF), another fumarate derivative, also directly inhibited biochemical markers of NLRP3 activation in LPS‐primed macrophages, mixed glia, OHSCs and human macrophages in response to nigericin and imiquimod, including ASC speck formation, caspase‐1 activation, gasdermin D cleavage and IL‐1β release. DMF, an approved treatment of multiple sclerosis, as well as DMI, 4OI and MMF, inhibited NLRP3 activation in macrophages in response to lysophosphatidylcholine, which is used to induce demyelination, suggesting a possible mechanism for DMF in multiple sclerosis through NLRP3 inhibition. The derivatives also reduced pro‐IL‐1α cleavage in response to the calcium ionophore ionomycin. Together, these findings reveal the immunometabolic regulation of both the priming and activation steps of NLRP3 activation in macrophages. Furthermore, we highlight itaconate and fumarate derivatives as potential therapeutic options in NLRP3‐ and IL‐1α‐driven diseases, including in the brain. The effects of itaconate and fumarate derivatives on canonical NLRP3 inflammasome activation in macrophages and microglia were investigated. Itaconate and fumarate derivatives inhibited both the priming and activation steps of canonical NLRP3 activation in response to nigericin, imiquimod and lysophosphatidylcholine stimulation. The derivatives also reduced interleukin‐1α cleavage in response to ionomycin.
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DOI：
10.1074/jbc.m114.557561
发表时间：
2014-06-06
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
England H;Summersgill HR;Edye ME;Rothwell NJ;Brough D
通讯作者：
Brough D
影响因子：
29
作者：
Hooftman, Alexander;Angiari, Stefano;O'Neill, Luke A. J.
通讯作者：
O'Neill, Luke A. J.
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
64.8
作者：
Bambouskova M;Gorvel L;Lampropoulou V;Sergushichev A;Loginicheva E;Johnson K;Korenfeld D;Mathyer ME;Kim H;Huang LH;Duncan D;Bregman H;Keskin A;Santeford A;Apte RS;Sehgal R;Johnson B;Amarasinghe GK;Soares MP;Satoh T;Akira S;Hai T;de Guzman Strong C;Auclair K;Roddy TP;Biller SA;Jovanovic M;Klechevsky E;Stewart KM;Randolph GJ;Artyomov MN
通讯作者：
Artyomov MN
DOI：
10.1126/science.aan4665
发表时间：
2018-04-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kornberg MD;Bhargava P;Kim PM;Putluri V;Snowman AM;Putluri N;Calabresi PA;Snyder SH
通讯作者：
Snyder SH