Inflammation最新文献

Diabetic kidney disease (DKD), which is emerging as a pervasive global health concern and a considerable economic burden, is characterized by a detrimental effect on renal function and structure. Recent research indicates that the progression of DKD is facilitated by lipotoxic injury to tubular epithelial cells (TECs). However, the specific mechanisms that contribute to this cellular damage have yet to be fully elucidated. Our results revealed a significant upregulation of F2RL1 in vivo and in vitro models, which was positively correlated with the expression of inflammatory factors. Knockdown of F2RL1 significantly reduced inflammatory response in palmitate-stimulated HK-2 cells. Mechanistically, F2RL1 might exacerbate lipotoxicity-induced DKD through the modulation of the Hippo signaling pathway. Collectively, these findings suggest that modulating F2RL1 expression may be a strategic approach to mitigate the inflammatory damage to RTECs associated with DKD, potentially through its involvement in the Hippo signaling pathway. Given these findings, F2RL1 merits consideration as a candidate therapeutic target for DKD.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with systemic inflammation and vascular injury, which contribute to the development of acute respiratory syndrome (ARDS) and the mortality of COVID-19 infection. Moreover, multiorgan complications due to persistent endothelial dysfunction have been suspected as the cause of post-acute sequelae of SARS-CoV-2 infection. Therefore, elucidation of the vascular inflammatory effect of SARS-CoV-2 will increase our understanding of how endothelial cells (ECs) contribute to the short- and long-term consequences of SARS-CoV-2 infection. Here, we investigated the interaction of SARS-CoV-2 spike protein with human ECs from aortic (HAoEC) and pulmonary microvascular (HPMC) origins, cultured under physiological flow conditions. We showed that the SARS-CoV-2 spike protein triggers prolonged expression of cell adhesion markers in both ECs, similar to the effect of TNF-α. SARS-CoV-2 spike treatment also led to the release of various cytokines and chemokines observed in severe COVID-19 patients. Moreover, increased binding of leucocytes to the endothelial surface and a procoagulant state of the endothelium were observed. Transcriptomic profiles of SARS-CoV-2 spike-activated HPMC and HAoEC showed prolonged upregulation of genes and pathways associated with responses to virus, cytokine-mediated signaling, pattern recognition, as well as complement and coagulation pathways. Our findings support experimental and clinical observations of the vascular consequences of SARS-CoV-2 infection and highlight the importance of EC protection as one of the strategies to mitigate the severe effects as well as the possible post-acute complications of COVID-19 disease.

Microglia, the central nervous system's primary immune cells, play a key role in the progression of cerebral ischemic stroke, particularly through their involvement in pyroptosis. The long non-coding RNA taurine up-regulated gene 1 (Tug1) is elevated during ischemic stroke and is critical in driving post-stroke neuroinflammation. However, the underlying molecular mechanisms remain unclear. This study explores the biological role of Tug1 and its potential mechanisms in regulating pyroptosis in microglia. We utilized an in vivo photothrombosis (PT) mice model and an in vitro oxygen-glucose deprivation and reperfusion (OGD/R) BV2 cell model to explore the mechanisms underlying ischemic stroke. Initially, we assessed the expression levels of Tug1 in the OGD/R model in vitro and the PT model in vivo. Subsequently, we investigated the impact of Tug1 on microglial pyroptosis by knocking down Tug1, silencing the PTEN-induced putative kinase 1 (Pink1) expression, and employing the mitophagy inhibitor mdivi-1. Tug1 exacerbated microglial pyroptosis by inhibiting mitophagy in both in vivo and in vitro models. The increase in mitophagy observed following Tug1 knockdown was reversed by either silencing Pink1 expression or using the mitophagy inhibitor mdivi-1. This reversal resulted in exacerbated pyroptosis and worsened neurological damage. Further mechanistic studies revealed that Tug1 knockdown significantly reduced microglial pyroptosis and alleviated neuronal damage by enhancing PINK1/Parkin-mediated mitophagy. For the first time, this study reveals that Tug1 promotes hypoxia-induced microglial pyroptosis by inhibiting PINK1/Parkin-mediated mitophagy, potentially providing a promising therapeutic target for ischemic inflammatory injury.

The main pathogenic mechanism of HIV-associated neurocognitive disorders (HAND) is neuronal apoptosis induced by inflammatory mediators, in which microglial inflammation plays a crucial role. However, the exact pathogenic mechanism remains unclear. Previous studies have shown that the HIV-1 gp120 V3 loop can trigger inflammation in CHME-5 microglia. p62 is a post-translational modified multidomain protein that is involved in the regulation of autophagy and is closely related to neuroinflammation. In this study, we found that p62 knockout down-regulated the expression of MCP-1, IL-6 and COX-2, and improved the inflammation of HIV-1 gp120 V3 loop induced microglia, while overexpression of p62 up-regulated the expression of MCP-1, IL-6 and COX-2, and promoted the inflammation of microglia. In addition, protein kinase C (PKC) knockout down-regulated the expression of MCP-1, IL-6 and COX-2 and inhibited the activation of IKK/ NF-κ B pathway, while tumor necrosis factor receptor-associated factor 6 (TRAF6) knockout had no significant effect on the expression of MCP-1, IL-6 and COX-2. Co-immunoprecipitation showed that p62 was bound and interacted with PKC. Inhibition of IKK/ NF-κ B pathway can down-regulate the expression of MCP-1, IL-6 and COX-2, and improve the inflammatory response of microglia. Our research further found that inhibition of IKK/ NF-κ B can decrease the expression of Caspase-3 and reduce the apoptosis of neurons in the co-culture of CHME-5 microglia and primary mouse neurons. The results of this study suggest that HIV-1 gp120 V3 loop induced CHME-5 microglial inflammation may be activated by the direct binding of p62 and PKC through the IKK/ NF-κ B signaling pathway, and these findings provide an important reference for the prevention and treatment of HAND.

Microglia are highly specialized resident macrophages in the central nervous system that play a pivotal role in modulating neuroinflammation. Microglial plasticity is essential for their function, allowing them to polarize into proinflammatory M1-like or anti-inflammatory M2-like phenotypes. However, the mechanisms driving M1 and M2 microglial induction during retinal degeneration remain largely unexplored. In addition, drugs that regulate retinal microglial polarity have not been fully investigated. The synthetic glucocorticoid triamcinolone acetonide (TA) is widely utilized in ophthalmology clinics for its anti-inflammatory properties. Here, we investigated microglial polarity in a light-induced retinal degeneration mouse model, along with the effects and mechanisms of intravitreal injection of TA on microglial polarity, retinal inflammation, and visual function following light damage (LD). Our findings demonstrated that LD induced a pro-inflammatory M1 microglial signature, with levels of M1 marker proteins in the retina increasing in a time-dependent manner following LD. Intravitreal TA treatment mitigated LD-induced retinal inflammation, photoreceptor death, and retinal blood vessel leakage, and preserved retinal responsiveness to light stimuli. Mechanistically, TA suppressed the proinflammatory microglial phenotype while promoting the anti-inflammatory phenotype by activating the signal transducer and activator of transcription 6/arginase1 (STAT6/Arg1) signaling pathway. These results reveal a new mechanism by which TA protects the retina from LD by shifting microglia toward an anti-inflammatory state through the STAT6/Arg1 axis.

Intermittent fasting (IF) has been shown to ameliorate inflammation including DSS-induced colitis. It is well known that autophagy can limit inflammation and TFEB is a master transcriptional factor that regulates the processes of autophagy. However, whether TFEB is involved in the regulation of IF-mediated amelioration of inflammation and its mechanism remained unclear. In this study, we found that IF ameliorated DSS-induced colitis and induced TFEB. Nutrition deprivation induced TFEB puncta formation, which processes the characteristics of liquid-liquid phase separation (LLPS) showed by fluorescence recovery after photobleaching (FRAP) assay and 1,6-hexanediol treatment. We found the 24-33 amino acids of Coiled-Coil (CC) domain located in N terminus is essential for TFEB phase separation. Deletion of 24-33 amino acids within the CC domain inhibited TFEB-mediated target gene expression. In addition, we found transcription co-activators, EP300 and MED1, co-localized with TFEB condensate to formed a transcriptional hub that promotes the efficient expression of target genes. More importantly, TFEB inhibitor with ability to suppress TFEB puncta formation abolished the IF-mediated amelioration of DSS colitis. Together, these findings revealed a critical role of TFEB phase separation in the regulation of its transcriptional activity and anti-inflammatory functions induced by IF.

Neutrophil extracellular traps (NETs) play an important role in the inflammatory response and progressive joint destruction in rheumatoid arthritis (RA). Rhaponticin (Rha) is a stilbene glycoside compound with antioxidant and anti-inflammatory effects. This study aimed to investigate the therapeutic potential of Rha in RA, with a specific focus on its effects on NETs and on the underlying mechanisms of Rha. NETs formation induced by phorbol 12-myristate 13-acetate (PMA) and a collagen-induced arthritis (CIA) mouse model were implemented to evaluate the pharmacological effects of Rha in vitro and in vivo. The potential mechanism of Rha in improving RA was screened and verified using the SuperPred and DisGeNET databases. Disulfiram (a GSDMD inhibitor) and S100a8^cre GSDMD^fl/fl mice were used to confirm whether GSDMD is key to the role of Rha. The findings demonstrate that Rha significantly inhibited reactive oxygen species and NETs production in PMA-activated neutrophils. In vivo, Rha treatment significantly relieved joint symptoms in CIA mice and NETs production. Mechanistically, Rha reduced NETs production via inhibition of NLRP3/GSDMD activation. Neutrophil-specific GSDMD depletion eliminated the effects of Rha on NETs production in vitro. Disulfiram eliminated the effects of Rha on the inhibition of NETs production and alleviated joint inflammation in mice in vivo and in vitro. Overall, our results indicated that Rha exerts a protective effect against CIA by inhibiting NETs production through the NLRP3/GSDMD pathway. The results of this study provide new strategies for treating RA.

Fibroblast growth factor 21 (FGF21) modulates the inflammatory response in a range of pathological conditions. However, whether FGF21 modulates asthma remains unexplored. This study sought to investigate its function in asthma using an ovalbumin (OVA)-induced mouse model. Levels of FGF21 were observed to be elevated in mice exhibiting asthmatic symptoms. FGF21 knockout (KO) mice exhibited exacerbated asthmatic pathologies, marked by heightened infiltration of inflammatory cells and elevated release of inflammatory cytokine, compared to wild-type (WT) mice with OVA challenge. Adeno-associated virus (AAV)-mediated overexpression of FGF21 significantly reversed asthmatic pathologies in both WT and FGF21 KO mice. Activated NLRP3 inflammasome was observed in WT mice following OVA challenge, and this response was intensified in FGF21 KO mice, manifested by an upregulation of NLRP3, ASC, cleaved Caspase-1, cleaved Gasdermin D (GSDMD), IL-1β, and IL-18. Pharmacological suppression of NLRP3 ameliorated the aggravated asthmatic pathologies observed in FGF21 KO mice after OVA challenge. Overall, the present work underscores the pivotal function of FGF21 in the pathogenesis of asthma and suggests that FGF21 could serve as a potential target for therapeutic interventions.

Endoplasmic reticulum stress (ERs) is implicated in antitumor immunity. However, the exact role of ERs in mediating the effects of dendritic cells (DCs) is not unclear. In this study, we explored the role of exosomes derived from ER-stressed hepatocellular carcinoma (HCC) cells in the antitumor effects of DCs and the precise underlying mechanism. We found that ER-stressed HCC cells secreted more exosomes (EXO-TM) than those without ER stress (EXO-CON) and that exosomes were effectively taken up by DCs. EXO-TM significantly promoted DCs maturation, as demonstrated by the increased expression of HLA-ABC, CD83, CD80, CD86, and pro-inflammatory cytokines and the decreased expression of IL-10. Moreover, EXO-TM pulsed DCs (DC_EXO-TM) significantly enhanced T lymphocyte-mediated lysis against several types of tumor cells by promoting the proliferation of CD3⁺CD8⁺ T cells and increasing the expression of INF-γ both in vitro and in vivo. Mechanistically, we found that heat shock protein (HSP) 90 was more significantly enriched in EXO-TM than in EXO-CON cells, and the knockdown of HSP90 remarkably reversed EXO-TM-mediated DC activation. Our results suggest that exosomes derived from ER-stressed HCC cells could enhance the antitumor effect of DC-mediated T lymphocytes, which may be related to the large amount of HSP90 carried in the exosomes. Therefore, regulating the HSP90 carrying capacity of tumor exosomes may be an effective immunotherapy strategy.