Inflammation最新文献

Severe acute pancreatitis (SAP) is a life-threatening inflammatory condition driven by macrophage-mediated oxidative stress and metabolic dysregulation. While bioactive peptides such as melittin show anti-inflammatory potential, their clinical application is limited by cytotoxicity and unclear mechanisms. In this study, we developed HMLT, a melittin-derived peptide with histidine substitutions designed to reduce cytotoxicity. Compared with native melittin, HMLT exhibited significantly lower cytotoxicity in RAW264.7 macrophages while maintaining potent anti-inflammatory activity, as demonstrated by reduced TNF-α release and downregulated expression of TNF-α, IL-6 and IL-1β. Flow cytometry analysis revealed that HMLT reduced ROS accumulation and protected mitochondrial membrane potential in LPS-stimulated macrophages. Additionally, HMLT decreased nitric oxide release and suppressed inducible nitric oxide synthase expression. Metabolomic analysis showed that HMLT restored metabolic balance by increasing endogenous antioxidants including O-acetylcarnitine and ornithine, while downregulating glycolytic intermediates such as phosphoenolpyruvic acid, 2-phospho-D-glyceric acid and 3-phosphoglyceric acid. In a caerulein and LPS-induced murine SAP model, HMLT administration significantly alleviated pancreatic injury, as evidenced by reduced serum amylase and lipase levels, diminished edema. Further mechanistic studies revealed that HMLT inhibited TNF-α secretion and suppressed PKM2-mediated glycolysis in M2-like macrophages. Collectively, these findings demonstrate that HMLT overcomes the toxicity limitations of native melittin and ameliorates SAP through coordinated restoration of oxidative homeostasis and metabolic reprogramming in macrophages, highlighting its promise as a lead compound for SAP treatment.

Renal ischemia-reperfusion injury (IRI) triggers a sterile immune response, primarily mediated by the innate immune system. Interleukin-33 (IL-33) promotes neutrophil infiltration during inflammatory processes, and neutrophils play a critical role in renal IRI pathology. This study aims to elucidate the mechanisms of IL-33 in neutrophil extracellular trap (NET) formation during renal IRI. The association between IL-33 and NET formation was investigated using suppression of tumorigenicity 2 (ST2) knockout (KO) mice, RNA sequencing, and pharmacological interventions. Results revealed that compared with preoperative levels, postoperative serum IL-33 and NET formation were elevated and positively correlated in patients undergoing renal transplantation. Similarly, the mouse model of renal I/R exhibited increased IL-33 expression and NET formation, which were also highly correlated. Administration of recombinant IL-33 during renal I/R enhanced NET formation and worsened renal IRI. However, treatment with an anti-IL-33 monoclonal antibody decreased NET formation and mitigated renal IRI. ST2 KO mice exhibited reduced NET formation and increased protection against renal IRI compared to control mice after renal I/R. In vitro studies showed that IL-33 dose-dependently promoted NET formation in neutrophils. Mechanistically, IL-33-induced NET formation was markedly reduced in ST2 KO mouse-derived neutrophils. Furthermore, RNA sequencing results revealed that IL-33-induced NET formation was mediated via ST2/ PI3K/Akt and ST2/peptidylarginine deiminase 4 (PAD4) signaling pathways. Inhibition of these pathways significantly suppressed IL-33-induced NET formation. In summary, this study demonstrates that IL-33/ST2 signaling exacerbates renal IRI by amplifying NETs. Targeting the IL-33/ST2 axis and inhibiting NET formation offers promising therapeutic strategies for preventing and treating renal IRI.

Despite the well-recognized role of the deubiquitinase CYLD in the pathogenesis of tumors and certain inflammatory diseases, its specific function and regulatory mechanisms in psoriasis remain unclear. Thus, we first analyzed CYLD expression differences between psoriatic patients and healthy controls using skin samples from the GEO database and validated its expression dynamics in an imiquimod (IMQ)-induced mouse model. Then, we systematically evaluated the effects of CYLD deficiency on psoriasiform inflammation through histopathology, immunohistochemistry, RNA sequencing, and immunofluorescence analyses using Cyld knockout (Cyld^-/-) mice, and employed bioinformatics approaches including CIBERSORT and Weighted Gene Co-expression Network Analysis (WGCNA) to further explore the associations between CYLD and neutrophil-related pathways and genes. The results showed that CYLD expression was significantly upregulated in lesional skin of psoriasis patients; Cyld^-/- mice displayed more severe psoriasiform symptoms (enhanced epidermal thickening, increased neutrophil infiltration, significantly augmented formation of neutrophil extracellular traps [NETs]); CYLD deficiency led to excessive activation of the NF-κB signaling pathway and upregulated expression of various pro-inflammatory cytokines and chemokines. Bioinformatics analyses confirmed CYLD was closely associated with pathways related to neutrophil migration and activation. These findings lead to the conclusion that CYLD plays a crucial negative regulatory role in psoriasis by inhibiting NF-κB-mediated neutrophil activation and NETs formation, so targeted activation of CYLD may represent a promising novel therapeutic strategy for psoriasis.

Sepsis-induced acute lung injury is a significant clinical challenge with high morbidity and mortality rates. Currently, no effective therapeutic interventions are available. The aim of this study was to elucidate the role and underlying mechanisms of Caveolin-2 in sepsis-induced acute lung injury. To this end, a Caveolin-2 knockdown model was utilized both in vivo and in vitro, facilitating a comprehensive evaluation of several parameters, including lung tissue injury, inflammatory responses, oxidative stress markers, changes in apoptotic protein expression, and indicators of macrophage polarization. Additionally, the study investigated alterations in proteins associated with the Hippo signaling pathway and assessed the effects of Hippo pathway inhibitors on apoptosis and polarization. Our results indicate that the knockdown of Caveolin-2 facilitates the polarization of macrophages towards the protective M2 macrophage polarization and mitigates macrophage apoptosis. This process is associated with a reduction in oxidative stress and inflammatory responses, culminating in the activation of the Hippo signaling pathway. Conversely, the overexpression of Caveolin-2 intensifies inflammation and oxidative damage, while promoting apoptosis and M1 macrophage polarization. Our findings provide novel insights into the role of Caveolin-2 and Hippo signal pathway in sepsis-induced acute lung injury and establish a foundation for future research and the development of potential therapeutic strategies.

Sepsis-associated neuroinflammation contributes to long-term neurological deficits, but therapeutic strategies remain limited. Here, we demonstrate that minocycline (Mino) mitigates sepsis-induced neuroinjury by upregulating inositol polyphosphate-5-phosphatase D (INPP5D), thereby suppressing microglia-mediated central amygdala (CeA) neuronal hyperactivation. In a cecal ligation and puncture (CLP)-induced septic mouse model, Mino treatment improved behavioral deficits and reduced neuroinflammation. Multi-omics analyses identified INPP5D as a critical downstream effector of Mino's neuroprotection. In vitro, Mino enhanced INPP5D expression in microglia, concurrently inhibiting pro-inflammatory activation, promoting autophagy, restoring mitochondrial function, and augmenting antioxidant responses. Microglia-neuron co-culture experiments revealed that Mino-dependent INPP5D upregulation attenuated CeA neuronal hyperexcitability and dendritic spine loss. Crucially, in vivo silencing of INPP5D or autophagy blockade abolished Mino's protective effects, confirming the INPP5D-autophagy axis as indispensable for neuroprotection. Our findings unveil a novel mechanism whereby Mino rescues sepsis-induced neuroinjury via INPP5D-mediated modulation of microglial activation and CeA neuronal dysfunction, offering a promising therapeutic target for sepsis-associated encephalopathy.

Acute pancreatitis (AP) is an inflammatory disorder that escalate rapidly from localized pancreatic injury to systemic inflammation and multi-organ failure. Dysregulated innate immunity is central to AP pathogenesis: acinar cell injury releases damage-associated molecular patterns (DAMPs), triggering an inflammatory cascade. However, the molecular mediators that amplify and sustain systemic immune activation remain elusive. Here, through integrated bulk and single-cell transcriptomes analyses of human AP patients and murine models, we identified N-myc and STAT interactor (NMI) as a DAMP mediator consistently upregulated in the pancreas, circulation, and distant organs during AP. NMI expression was enriched in macrophages and neutrophils, and circulating NMI distinguished AP patients from healthy controls with high diagnostic accuracy. Mechanistically, recombinant NMI directly activated macrophages, inducing rapid PI3K-AKT phosphorylation and secretion of pro-inflammatory cytokines IL-6 and TNF, while single-cell communication analysis revealed IL-6 as a dominant downstream effector. In vivo, both genetic ablation of Nmi and pharmacologic inhibition of PI3K-AKT signaling attenuated pancreatic injury, mitigated lung involvement, and reduced systemic cytokine release in severe AP(SAP). Collectively, these findings establish NMI as a mechanistic driver and biomarker of AP, with translational potential as a therapeutic target to curb excessive inflammation and improve outcomes.

Herpes simplex virus type 1 (HSV-1) triggers significant inflammation and immune dysregulation, particularly in immunocompromised hosts. MicroRNA-221 (miR-221) is implicated in viral pathogenesis and inflammatory responses, yet its role in HSV-1 infection remains undefined. This study demonstrates that miR-221 suppresses HSV-1 replication, with 100 nM miR-221 reducing plaque formation by approximately 70% and markedly decreasing infectious viral titers (TCID₅₀) in vitro. Mechanistically, bioinformatic analyses, dual-luciferase reporting, and RNA immunoprecipitation (RIP) confirmed CAMK2A, a calcium-signaling kinase, as a direct target of miR-221. KEGG pathway mapping linked miR-221 to calcium signaling, complement activation, and extracellular matrix interactions. In vivo, miR-221 overexpression in HSV-1-infected mouse corneas reduced pro-inflammatory cytokines (TNF-α, IL-6) and elevated anti-inflammatory IL-10, while enhancing CD8⁺ T-cell and NK-cell activation. Critically, it attenuated inflammatory cell infiltration and tissue apoptosis. CAMK2A inhibition synergistically amplified these antiviral and anti-inflammatory effects, whereas CAMK2A overexpression reversed them. We conclude that miR-221 restricts HSV-1 replication and modulates host inflammation by recruiting RISC to silence CAMK2A, thereby disrupting calcium signaling and promoting immune activation. These findings identify the miR-221/CAMK2A axis as a promising therapeutic target for HSV-1-induced inflammation.

Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, plays a critical role in the progression of asthma, yet its therapeutic modulation remains underexplored. Luteolin (Lut), a natural flavonoid known for its anti-inflammatory properties, presents a potential candidate for targeting ferroptosis in asthma. However, the precise mechanisms underlying its therapeutic effects are unclear. This study used a combination of bioinformatics, network pharmacology, molecular docking, and in vitro and in vivo experiments to investigate the role of luteolin in the treatment of ferroptosis in asthma. A collection of natural flavonoid compounds with high oral bioavailability and drug-like properties was assembled from the Chinese herbal medicine database. Through network pharmacology analysis, it was discovered that these flavonoids can effectively treat ferroptosis in asthma by regulating Arachidonic acid 15-lipoxygenase (ALOX15) and arachidonic acid metabolism. Further investigation through virtual docking revealed that luteolin is a key compound in the treatment of ferroptosis in asthma, targeting ALOX15. Molecular dynamics simulations demonstrated that the ALOX15-luteolin complex is stable and flexible. Cellular Thermal Shift Assay (CETSA) confirmed the thermal stability of luteolin and ALOX15, while Drug affinity response target stability (DARTS) assay showed that luteolin inhibits the proteolysis of ALOX15 by pronase. In in vitro experiments, it was observed that luteolin treatment reduced Fe²⁺ content and lipid ROS levels in a dose-dependent manner, while also downregulating ALOX15 and ACSL4 and upregulating SLC7A11 and GPX4, effectively alleviating ferroptosis induced by house dust mite (HDM) and lipopolysaccharide (LPS) in 16HBE cells. ALOX15 was specifically knocked down in 16HBE cells, and it was found that ALOX15 silencing and luteolin treatment could also inhibit ferroptosis in asthma. In vivo experiments and serum metabolomics analyses further confirmed that luteolin inhibits ferroptosis by suppressing ALOX15 expression and regulating arachidonic acid metabolism, ultimately alleviating asthma symptoms in mice. This study found that luteolin inhibited ALOX15-mediated ferroptosis in bronchial epithelial cells to alleviate asthma, highlighting the potential of luteolin as a promising therapeutic agent for asthma treatment.

Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus, involves immune complex deposition, inflammation, and kidney damage. Recent studies indicate that pyroptosis, a pro-inflammatory cell death process, drives renal injury in LN. This study intended to identify key pyroptosis-related genes in LN using datasets from the GEO database, encompassing glomerular, tubulointerstitial, and whole kidney tissues from LN patients. Identified differentially expressed genes related to pyroptosis and created a predictive model using univariate and LASSO regression analysis. LN patients were classified into subtypes through consensus clustering. Immune microenvironment characteristics and hallmark pathways were further analyzed. Using the WGCNA, key gene modules and hub genes were recognized, followed by an analysis of their clinical relevance and distribution patterns using the Nephroseq database and scRNA-seq data. Cellular experiments were conducted to validate the findings. We identified 26 differentially expressed pyroptosis-related genes in LN glomeruli and created a 10-gene model with high diagnostic accuracy (AUC: 0.968 for tubulointerstitium, 0.990 for whole kidney). Consensus clustering divided LN into two subtypes: subtype1, characterized by inflammation and immune activation, and subtype2, characterized by cellular metabolism. WGCNA highlighted the grey60 module linked to subtype1, and identified GBP2 and EIF2AK2 as hub genes. Cellular experiments showed that GBP2 and EIF2AK2 were upregulated in LPS-stimulated macrophages and glomerular endothelial cells, and their siRNA-mediated knockdown triggered a decline in pyroptosis-related marker expression, implying their possible role as therapeutic targets for modulating pyroptosis in LN. In conclusion, GBP2 and EIF2AK2 show potential as candidate molecules for targeted therapy in LN.