Classically activated mouse macrophages produce methylglyoxal that induces a TLR4- and RAGE-independent proinflammatory response.
Classically activated mouse macrophages produce methylglyoxal that induces a TLR4- and RAGE-independent proinflammatory response.
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经典激活的小鼠巨噬细胞产生甲基乙二醛，诱导 TLR4 和 RAGE 独立的促炎反应。
DOI：
10.1002/jlb.3a0520-745rr
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发表时间：
2021-03
影响因子：
5.5
通讯作者：
Vogel SN
中科院分区：
文献类型：
--
作者：
Prantner D;Nallar S;Richard K;Spiegel D;Collins KD;Vogel SN
高反应性化合物甲基乙二醛（MG）可通过与细胞大分子反应而对细胞和组织造成直接损伤。MG已被鉴定为与脓毒症诱导的死亡率增加相关的生物标志物。与手术后患者和健康对照相比，经历感染性休克的患者具有显著升高的循环MG水平。此外，MG与II型糖尿病和阿尔茨海默病的发展有关。由于MG是在糖酵解过程中产生的，我们假设MG可能是由经典活化的（M1）巨噬细胞产生的，可能有助于炎症反应。LPS和IFN-γ处理的巨噬细胞获得了M1表型（如M1标志物和增强的糖酵解所证明的），并形成了MG加合物MG-H1、MG-H2和MG-H3，使用MG修饰蛋白（甲基乙二醛5-氢-5-甲基咪唑酮）特异性抗体检测到这些加合物。在LPS处理的小鼠的肺中MG加合物也增加。用LPS和IFN-γ处理的巨噬细胞也表现出代谢MG的酶Glycosidase 1（Glo 1）的表达降低。浓度> 0.5 mM的外源性纯化MG对巨噬细胞有毒性;然而，0.3 mM的无毒剂量诱导TNF-α和IL-1β，尽管程度低于LPS刺激。尽管先前的证据表明MG-加合物可以通过“晚期糖基化终产物受体”（Receptor for Advanced Glycation Endproducts，RAGE）进行信号传导，但在原代巨噬细胞中，MG介导的细胞死亡和外源性MG诱导的细胞因子是RAGE非依赖性的。最后，RAGE缺陷型小鼠在注射致死性LPS后没有表现出显著的生存优势。总体而言，我们的证据表明，MG可能是由M1巨噬细胞在脓毒症期间产生的，随后IFN-γ依赖性下调Glo 1，导致过度旺盛的炎症。MG对巨噬细胞功能的细胞和分子作用，包括促进独立于炎症因子的炎症细胞因子诱导。
The highly reactive compound methylglyoxal (MG) can cause direct damage to cells and tissues by reacting with cellular macromolecules. MG has been identified as a biomarker associated with increased sepsis-induced mortality. Patients undergoing septic shock have significantly elevated circulating MG levels compared to post-operative patients and healthy controls. Furthermore, MG has been implicated in the development of Type II diabetes mellitus and Alzheimer’s Disease. Since MG is generated during glycolysis, we hypothesized that MG may be produced by classically activated (M1) macrophages, possibly contributing to the inflammatory response. LPS and IFN-γ-treated macrophages acquired an M1 phenotype (as evidenced by M1 markers and enhanced glycolysis) and formed MG-adducts, MG-H1, MG-H2, and MG-H3, that were detected using antibodies specific for MG-modified proteins (methylglyoxal 5-hydro-5-methylimidazolones). MG adducts were also increased in the lungs of LPS-treated mice. Macrophages treated with LPS and IFN-γ also exhibited decreased expression of Glyoxalase 1 (Glo1), an enzyme that metabolizes MG. Concentrations of exogenous, purified MG > 0.5 mM were toxic to macrophages; however, a nontoxic dose of 0.3 mM induced TNF-α and IL-1β, albeit to a lesser extent than LPS stimulation. Despite prior evidence that MG-adducts may signal through “Receptor for Advanced Glycation Endproducts” (RAGE), MG-mediated cell death and cytokine induction by exogenous MG was RAGE-independent in primary macrophages. Finally, RAGE-deficient mice did not exhibit a significant survival advantage following lethal LPS injection. Overall, our evidence suggests that MG may be produced by M1 macrophages during sepsis, following IFN-γ-dependent down regulation of Glo1, contributing to over-exuberant inflammation. Cellular and molecular effects of MG on macrophage function, including a role in promoting inflammatory cytokine induction independent of RAGE.