Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation

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葡萄膜炎并发白内障患者晶状体前囊膜中NLRP3炎症小体相关蛋白的表达和前囊膜超微结构改变

目的　探究葡萄膜炎并发白内障患者晶状体前囊膜中NLRP3炎症小体相关蛋白的表达和前囊膜超微结构改变。方法　随机选取2018年8月至2019年6月在我院诊治的葡萄膜炎并发白内障患者17例(22眼)作为试验组；老年性白内障患者10例(18眼)作为对照组。均于白内障超声乳化手术中环形撕囊获取前囊膜。采用免疫组织化学法检测两组患者晶状体前囊膜NLRP3炎症小体的三个组成结构NLRP3、Caspase-1和接头蛋白ASC的蛋白表达，并对前囊膜进行电镜观察。结果　两组患者晶状体前囊膜中均有NLRP3炎症小体相关蛋白的表达；试验组晶状体前囊膜中NLRP3、Caspase-1及接头蛋白ASC（光密度值分别为0.383±0.067、0.313±0.058、0.335±0.035）表达水平均明显高于对照组（光密度值分别为0.330±0.085、0.271±0.039、0.268±0.036）（均为P<0.05）。试验组患者前囊膜的晶状体上皮细胞可见明显的细胞核固缩，染色质浓缩边集，细胞核膜皱褶、轻度增宽，线粒体形态基本正常、部分线粒体嵴突消失，细胞质中可见典型的凋亡小体。对照组有轻度凋亡改变。结论　NLRP3炎症小体可能参与了葡萄膜炎并发白内障的发病过程，细胞凋亡是葡萄膜炎并发白内障的重要病理改变。     

The pyrin inflammasome and the Yersinia effector interaction

Pyrin is a cytosolic pattern-recognition receptor that normally functions as a guard to trigger capase-1 inflammasome assembly in response to bacterial toxins and effectors that inactivate RhoA. The MEFV gene encoding human pyrin is preferentially expressed in phagocytes. Key domains in pyrin include a pyrin domain (PYD), a linker region, and a B30.2 domain. Binding of ASC to pyrin by a PYD-PYD interaction triggers inflammasome assembly. Pyrin is held in an inactive conformation by negative regulation mechanisms to avoid premature inflammasome assembly. One mechanism of negative regulation involves phosphorylation of the linker by PRK kinase which in turn is positively regulated by active RhoA. The B30.2 domain also negatively regulates pyrin. Gain of function mutations in MEFV responsible for the autoinflammatory disease Familial Mediterranean Fever (FMF) map to exon 10 encoding the B30.2 domain. Insights into pyrin regulation have come from studies of several Yersinia effectors, which are injected into phagocytes and interact with the RhoA-PRK-pyrin axis during infection. Two effectors, YopE and YopT, inactivate RhoA to disrupt phagocytic signaling. To counteract an effector-triggered immune response, a third effector, YopM, binds to and inhibits pyrin by hijacking PRK and RSK and directing linker phosphorylation. Inhibition of pyrin by YopM is required for virulence of Yersinia pestis, the agent of plague. Recent results from infection studies with human phagocytes and mice producing pyrin B30.2 FMF variants show that gain of function MEFV mutations bypass inhibition by YopM. Population genetic data suggest that MEFV mutations were selected for in individuals of Mediterranean decent during historic plague pandemics. This review discusses current concepts of pyrin regulation and its interaction with Yersinia effectors.     

NLRP3 inflammasome and glia maturation factor coordinately regulate neuroinflammation and neuronal loss in MPTP mouse model of Parkinson’s disease

Neuroinflammation plays an active role in the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease (PD). Earlier studies from this laboratory showed that glia maturation factor (GMF), a proinflammatory mediator; is up-regulated in the brain in neurodegenerative diseases and that deficiency of GMF showed decreased production of IL-1β and improved behavioral abnormalities in mouse model of PD. However, the mechanisms linking GMF and dopaminergic neuronal death have not been completely explored. In the present study, we have investigated the expression of NLRP3 inflammasome and caspase-1 in the substantia nigra (SN) of human PD and non-PD brains by immunohistochemistry. Wild-type (WT) and GMF^−/− (GMF knock-out) mice were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP) and the brains were isolated for neurochemical and morphological examinations. NLRP3 and caspase-1 positive cells were found significantly increased in PD when compared to non-PD control brains. Moreover, GMF co-localized with α-Synuclein within reactive astrocytes in the midbrain of PD. Mice treated with MPTP exhibit glial activation-induced inflammation, and nigrostriatal dopaminergic neurodegeneration. Interestingly, increased expression of the inflammasome components in astrocytes and microglia observed in the SN of MPTP-treated WT mice were significantly reduced in GMF^−/− mice. Additionally, we show that NLRP3 activation in microglia leads to translocation of GMF and NLRP3 to the mitochondria. We conclude that downregulation of GMF may have beneficial effects in prevention of PD by modulating the cytotoxic functions of microglia and astrocytes through reduced activation of the NLRP3 inflammasome; a major contributor of neuroinflammation in the CNS.     

Ghrelin attenuates secondary brain injury following intracerebral hemorrhage by inhibiting NLRP3 inflammasome activation and promoting Nrf2/ARE signaling pathway in mice

Ghrelin, a brain-gut peptide, has been proven to exert neuroprotection in different kinds of neurological diseases; however, its role and the potential molecular mechanisms in secondary brain injury (SBI) after intracerebral hemorrhage (ICH) are still unknown. In this study, we investigate whether treatment with ghrelin may attenuate SBI in a murine ICH model, and if so, whether the neuroprotective effects are due to the inhibition of nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation and promotion of nuclear factor-E2-related factor 2 (Nrf2)/antioxidative response element (ARE) signaling pathway. Stereotactically intrastriatal infusion of autologous blood was performed to mimic ICH. Ghrelin was given intraperitoneally immediately following ICH and again 1 h later. Results showed that ghrelin attenuated neurobehavioral deficits, brain edema, hematoma volume, and perihematomal cell death post-ICH. Ghrelin inhibited the NLRP3 inflammasome activation and subsequently suppressed the neuroinflammatory response as evidenced by reduced microglia activation, neutrophil infiltration, and pro-inflammatory mediators release after ICH. Additionally, ghrelin alleviated ICH-induced oxidative stress according to the chemiluminescence of luminol and lucigenin, malondialdehyde (MDA) content, and total superoxide dismutase (SOD) activity assays. These changes were accompanied by upregulation of Nrf2 expression, Nrf2 nuclear accumulation, and enhanced Nrf2 DNA binding activity, as well as by increased expressions of Nrf2 downstream target antioxidative genes, including NAD(P)H quinine oxidoreductase-1 (NQO1), glutathione cysteine ligase regulatory subunit (GCLC), and glutathione cysteine ligase modulatory subunit (GCLM). Together, our data suggested that ghrelin protected against ICH-induced SBI by inhibiting NLRP3 inflammasome activation and promoting Nrf2/ARE signaling pathway.     

NLRP3 inflammasome: a new therapeutic target for high-risk reproductive disorders?

The NOD-like receptor protein 3 (NLRP3) inflammasome is a key regulator of the host''s immune response, and many immune and metabolic disorders are linked to its activation. This review aimed to investigate and clarify the relationship between this inflammasome and high-risk reproductive disorders. Papers cited here were retrieved from PubMed up to August 2020 using the keywords “NLRP3” or “NALP3”, “caspase-1”, “endometriosis”, “gestational diabetes”, “interleukin (IL)-18”, “IL-1β”, “pre-eclampsia (PE)”, “preterm birth”, “polycystic ovarian syndrome (PCOS)”, “recurrent spontaneous abortion (RSA)”, and combinations of these terms. The results show that NLRP3 inflammasome is associated with various high-risk reproductive disorders and many inflammatory factors are secreted during its activation, such as IL-1β induced during the development of endometriosis. PCOS is also associated with activation of the NLRP3 inflammasome, especially in overweight patients. It also participates in the pathogenesis of RSA and is activated in fetal membranes before preterm birth. The placentas of pregnant women with PE show higher expression of the NLRP3 inflammasome, and gestational diabetes mellitus occurs simultaneously with its activation. Current evidence suggest that the NLRP3 inflammasome plays an important role in female reproductive disorders. New treatment and management methods targeting it might help reduce the incidence of such disorders and improve neonatal outcomes.     

钙离子信号介导Nod样受体蛋白炎性小体激活的研究进展

Nod样受体蛋白（Nod-like receptor protein 3, NLRP3）炎性小体可识别多种病原体及细胞损伤,诱导分泌白细胞介素1β（interleukin-1β, IL-1β）、IL-18,调节炎症反应,是固有免疫系统的重要组成部分。近年研究表明,钙离子（Ca²⁺）信号参与多种NLRP3激动剂诱导的NLRP3炎性小体激活过程,并与相关疾病的发生密切相关。本文综述了有关钙离子与NLRP3炎性小体的相关研究,重点关注钙离子信号在NLRP3炎性小体激活和调节中的潜在作用,为治疗NLRP3炎性小体驱动的炎症性疾病提供新思路。