Inflammation最新文献

Excessive formation of neutrophil extracellular traps (NETs) has been shown to exacerbate inflammatory injury and organ damage in patients with sepsis. Circular RNAs (circRNAs) abnormally expressed in immune cells of sepsis patients, and play an important role in the pathogenesis of dysregulated immune responses. However, the functions of circRNAs in NET formation during sepsis remain unknown. Here, we identified circIRAK3, a novel circRNA that was upregulated in peripheral blood neutrophils of sepsis patients. Combining clinical data, we revealed that elevated circIRAK3 was positively correlated with blood NET levels. Furthermore, knockdown and overexpression in differentiated HL-60 (dHL-60) neutrophil-like cells demonstrated that circIRAK3 promoted NET formation. In addition, we found that circIRAK3 promoted NET formation via positively regulating elastase expression in dHL-60 cells when treated with inflammatory stimuli. Mechanistically, circIRAK3 directly interacted with ELAVL1 to improve ELANE mRNA stability and consequently promote elastase protein expression. In summary, our study reveals that circIRAK3 promotes NET formation in sepsis by increasing ELANE mRNA levels.

Depression is the leading cause of disability worldwide and places a significant burden on society. Neuroinflammation is closely associated with the pathophysiology of depression. Increasing evidence suggests that astrocytes, as the most abundant glial cells in the brain, are involved in the occurrence and development of depression due to morphological abnormalities and dysfunction. Astrocytes express the NOD-like receptor protein 2 (NLRP2) and NLRP3 inflammasomes, and the activation of inflammasomes induces pyroptosis. Ghrelin, a gastrointestinal peptide, plays vital role in regulating inflammation and alleviating stress. Therefore, we proposed a hypothesis that ghrelin inhibits the activation of inflammasomes on astrocytes, reduces pyroptosis, and consequently prevents depression. We used lipopolysaccharide (LPS)-induced mouse depression model and cultured primary astrocytes in vitro to explore the mechanism of the antidepressant effect of ghrelin. Our results showed that ghrelin effectively inhibited acute inflammatory responses and damage in the hippocampus and prefrontal cortex. The activation of NLRP2 and NLRP3 in astrocytes induced by LPS was significantly inhibited by ghrelin. Pretreatment with ghrelin effectively suppressed LPS-induced upregulation of pyroptosis-related proteins and mRNA. Ghrelin alleviated cell membrane pore formation and cell swelling, ultimately improved LPS-induced depression-like behavior. In vitro, ghrelin prevented the LPS-induced upregulation of pyroptosis-related proteins and mRNA expression in astrocytes, and inhibited the initiation and assembly of NLRP2 and NLRP3. Ghrelin exhibits antidepressant effects, inhibits inflammasomes activation in astrocytes, and prevents pyroptosis, suggesting a novel strategy for treating depression. This groundbreaking study reveals new avenues for targeting potential therapeutic interventions to alleviate depression.

5-aminolevulinic acid (5-ALA) is an amino acid essential for the synthesis of heme, which is important for various cellular functions, including the mitochondrial electron transport chain. We previously established heterozygous knockout mice (Alas1^+/-) for 5-ALA synthase 1 (ALAS1), the rate-limiting enzyme for 5-ALA synthesis, and reported that the mice developed non-obese insulin-resistant diabetes. In the present study, we used these mice to analyze the role of 5-ALA in the immune system. Using a lipopolysaccharide (LPS)-induced septic shock model, Alas1^+/- mice showed reduced mortality compared to wild-type (WT) mice. In this model experiment, the plasma concentration of inflammatory cytokines such as tumor necrosis factor α (TNFα) and interleukin-6 (IL-6), and the chemokine monocyte chemoattractant protein-1 (MCP1) decreased in Alas1^+/- mice compared that in WT mice, and inflammatory cell infiltration into the peritoneal cavity was also decreased. In ex vivo experiments, exogenous 5-ALA pretreatment enhanced LPS-induced TNFα and IL-6 production from peripheral blood leukocytes of Alas1^+/- mice. Additionally, 5-ALA pretreatment enhanced LPS-induced activation of inflammatory cytokine genes in innate immune cells. Interestingly, the phagocytosis and reactive oxygen species (ROS) producing abilities of neutrophils were clearly hampered in Alas1^+/- mice compared to WT mice, but after 2 weeks of 5-ALA administration to Alas1^+/- mice, both abilities were significantly recovered up to the level in WT mice. These results reveal that 5-ALA is essential for the function of innate immune cells. Because 5-ALA can be supplemented orally, it has the potential to be used as a drug to restore innate immune function.

Acute pancreatitis (AP) is a common acute inflammatory abdominal condition. Severe acute pancreatitis (SAP) can provoke a systemic inflammatory response and lead to multiple organ failure. The S100A9 protein, recognized as a major inflammatory biomarker, plays a significant role in both infection and inflammatory responses. Despite its known role in inflammation, the precise role of S100A9 in AP remains poorly understood. This study aimed to elucidate the potential role of S100A9 in AP and investigate the underlying mechanism. We employed a mouse model of AP and the AR42J cell line to investigate the functional role of S100A9. The effect of S100A9 on pancreatic injury and the expression of inflammatory factors (IL-6, IL-1β, and TNF-α) was assessed through targeted inhibition of S100A9 expression in the mouse model of AP. Furthermore, the modulatory effect of cerulein-induced inflammatory responses on AR42J cells was assessed after adding the S100A9 recombinant protein. In the mouse model of AP, targeted inhibition of S100A9 markedly ameliorated pancreatic injury and significantly decreased the expression levels of IL-6, IL-1β, and TNF-α. Moreover, increased levels of S100A9 were positively correlated with elevated expression of receptor for advanced glycation endproducts (RAGE) in pancreatic acinar cells. In AR42J cells, the introduction of S100A9 recombinant protein enhanced RAGE expression and exacerbated cerulein-induced inflammatory response. S100A9 inhibition significantly alleviated the pancreatic inflammatory response by downregulating RAGE expression, thereby improving AP.

Our previous study has shown that neutrophil extracellular traps (NETs) were associated with idiopathic inflammatory myopathy-related interstitial lung disease (IIM-ILD). Colchicine plays an anti-inflammatory role mainly by inhibiting the activity and chemotaxis of neutrophils. This study aims to verify therapeutic effects and mechanism of colchicine in IIM-ILD. 20 experimental autoimmune myositis (EAM) model mice were randomly divided into EAM group, colchicine groups (1, 2 mg/kg) and Cl-amidine group (positive control), five mice in the control group received sham modeling procedure. After 5 weeks, the mice were sacrificed to evaluate the degree of pulmonary interstitial lesions and the formation of NETs. Human neutrophils were pretreated with colchicine (40 nmol/L) and stimulated to form NETs. Human pulmonary microvascular endothelial cells (HPMECs) were pretreated with colchicine and stimulated with NETs, and markers of inflammation and pyroptosis were detected. Pathological staining of lung tissue showed that severity of ILD and NETs infiltration were significantly alleviated in colchicine groups (P < 0.01) and in the Cl-amidine group (P < 0.01), and the serum level of NETs was also significantly decreased in colchicine groups (P < 0.05) and in the Cl-amidine group (P < 0.05). Colchicine intervention significantly attenuated PMA-induced NETs formation in vitro (P < 0.0001). Colchicine intervention significantly reduced marker expressions of inflammasome and pyroptosis in HPMECs stimulated by NETs and in the lung tissue of EAM mice. Colchicine can alleviate ILD in EAM mice by inhibiting NETs formation, inflammasome activation and endothelial cell pyroptosis. These findings provide a basis for targeting NETs and colchicine administration in the treatment of myositis-associated ILD.

Multiple sclerosis (MS) and inflammatory bowel disease (IBD) are both autoimmune disorders caused by dysregulated immune responses. Still, there is a growing awareness of the comorbidity between MS and IBD. However, the shared pathophysiological mechanisms between these two diseases are still lacking. RNA sequencing datasets (GSE126124, GSE9686, GSE36807, GSE21942) were analyzed to identify the shared differential expressed genes (DEGs) for IBD and experimental allergic encephalomyelitis (EAE). Other datasets (GSE17048, GSE75214, and GSE16879) were downloaded for further verification and analysis. Shared pathways and regulatory networks were explored based on these DEGs. The single-cell transcriptome of central nervous system (CNS) immune cells sequenced from EAE brains and the public datasets of IBD (PRJCA003980) were analyzed for the immune characteristics of the shared DEGs. Mass cytometry by time-of-flight (CyTOF) of peripheral blood mononuclear cells (PBMCs) was performed for the systematic immune response in the EAE model. Machine learning algorithms were also used to identify the diagnostic biomarkers of MS. We identified 74 common DEGs from the selected RNA sequencing datasets, and single-cell RNA data of the intestinal tissues of IBD patients showed that 56 of 74 DEGs were highly enriched in IL1B⁺ macrophages. These 56 DEGs, defined as inflammation-related DEGs (IRGs), were also highly expressed in pro-inflammatory macrophages of EAE mice and MS patients. The abundance of systematic CD14⁺ monocytes was validated by CyTOF data. These IRGs were highly enriched in immune response, NOD-like receptor signaling pathway, IL-18 signaling pathway, and other related pathways. In addition, 'AddModuleScore_UCell' analysis further validated that these IRGs (such as IL1B, S100A8, and other inflammatory factors) are highly expressed mainly in pro-inflammatory macrophages, which play an essential role in pro-inflammatory activation in IBD and multiple sclerosis, such as IL-17 signaling pathway, NF-kappa B signaling pathway, and TNF signaling pathway. Finally, suppressors of cytokine signaling 3(SOCS3) and formyl peptide receptor 2(FPR2) were identified as potential biomarkers by machine learning. Two genes were highly expressed in pro-inflammatory macrophages of IBD and MS disease compared to control, and other datasets and experiments further revealed that SOCS3 and FPR2 were highly expressed in IBD and EAE samples. These shared IRGs, which encode inflammatory cytokines, exhibit high expression levels in inflammatory macrophages in IBD and may play a significant role in the inflammatory cytokine storm in MS patients. Two potential biomarkers, SOCS3 and FPR2, were screened out with great diagnostic value for MS and IBD.

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by stenosis or occlusion of the internal carotid artery, thus leading to ischaemic and haemorrhagic strokes. Although genetic studies have identified ring finger protein 213 (RNF213) as a susceptibility gene, the low disease penetrance suggests that a secondary trigger, such as infection, may initiate disease onset. This study aimed to characterize the innate immune cell profile of peripheral blood mononuclear cells (PBMCs) of MMD patients via mass cytometry (CyTOF). Blood samples from 10 MMD patients and 10 healthy controls were analysed, with a focus on natural killer (NK) cells, monocytes, and dendritic cells (DCs). The results revealed significant changes in the NK and monocyte subpopulations in MMD patients; specifically, there was a decrease in the CD56^dimCD16^- NK03 subset and an increase in CD163^high classical monocytes, thus indicating compromised microbial defences and heightened inflammation. Additionally, significant changes were observed in DC subpopulations, including an increase in CCR7⁺ mature DCs and a decrease in CD141⁺ and CD1c⁺ DCs. Overactivation of the TLR/MyD88/NF-κB pathway was observed in most innate immune cells, thus indicating its potential role in disease progression. These findings provide novel insights into immune dysfunction in MMD and highlight potential therapeutic targets.

Tripartite motif-containing protein 31 (Trim31) is known to be involved in various pathological conditions, including heart diseases. Nonetheless, its specific involvement in heart failure (HF) has yet to be determined. In this study, we examined the function and mechanism of Trim31 in HF by using mice with cardiac-specific knockout (cKO) of Trim31. The HF mouse model was induced via the subcutaneous injection of isoproterenol (ISO). We observed a decrease in Trim31 expression in the heart tissues of mice with HF. Compared with wild-type (WT) mice, Trim31 cKO mice presented more severe characteristics of HF, including worsened cardiac dysfunction, hypertrophy, and fibrosis. However, these symptoms in Trim31 cKO mice were significantly reversed when they received an intramyocardial injection of recombinant adeno-associated virus (AAV) expressing Trim31. Excessive activation of the NLRP3 inflammasome, manifested by increased levels of NLRP3, ASC, cleaved Caspase-1, cleaved GSDMD, IL-1β, and IL-18, was observed in Trim31 cKO mice with HF. However, Trim31 overexpression effectively reversed the NLRP3 inflammasome activation in Trim31 cKO mice with HF. Selective inhibition of the NLRP3 inflammasome with the NLRP3 inhibitor MCC950 effectively reversed the worsened cardiac dysfunction, hypertrophy, and fibrosis observed in Trim31 cKO mice with HF. Overall, the findings from this study reveal a crucial role of Trim31 in HF. Trim31 deficiency may contribute to the progression of HF by promoting cardiac hypertrophy, fibrosis, and inflammation by facilitating the activation of the NLRP3 inflammasome. Therefore, Trim31 may hold significant potential as a therapeutic target for the treatment of HF.

Indole-3-carboxaldehyde (3-IAld), a tryptophan metabolite derived from gut microbiota, has been reported to protect the intestine against radiation injury. This study aimed to clarify the role of Bifidobacterium longum (B. longum) and its metabolite indole-3-carboxaldehyde (3-IAld) in the pathophysiology of intestinal ischemia/reperfusion (II/R) injury. Superior mesenteric artery occlusion and reperfusion were performed to establish II/R mice, and pathological injury in II/R mice was evaluated. II/R mice showed impaired gut microbiota diversity and reduced abundance of B. longum in the intestines. Transplantation of B. longum mitigated II/R injury by protecting the integrity of the intestinal barrier and reducing inflammatory response. The 3-IAld level increased after transplantation of B. longum, and 3-IAld treatment inhibited the inflammatory response of bone marrow-derived macrophages (BMDM). Histone deacetylase 3 (HDAC3) was a target of 3-IAld, and HDAC3 was translocated to mitochondria to promote mitochondrial fatty acid oxidation (FAO) during macrophage inflammasome formation. HDAC3 overexpression promoted the formation of macrophage inflammasomes in intestinal tissues. Overall, this study confirmed the beneficial effects of B. longum in combating II/R injury through HDAC3-mediated control of mitochondrial FAO and macrophage inflammasome formation via 3-IAld.