Inflammation最新文献

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a vital regulator of inflammation and innate immune response. The aim of this study was to evaluate the potential of MALT1 knockdown for attenuating lipopolysaccharide (LPS)-induced inflammation. C57BL/6 mice received tail vein injection of knockdown control or Malt1 shRNA, followed by intraperitoneal injection of LPS two weeks later. After 24 h of LPS injection, the mice were euthanized for further analysis. The peripheral naïve CD4⁺ T cells of mice were isolated, treated with Malt1 overexpression vectors or Malt1 shRNA with or without nuclear factor-κB (NF-κB) activator (PMA) or inhibitor (BAY), under the presence of LPS. MALT1 knockdown alleviated the injuries of kidney and lung tissues, reduced the serum levels of proinflammatory cytokines, and decreased the proportions of T-helper (Th)1 and Th17 cells in mice. The phosphorylation of transforming growth factor beta-activated kinase 1 (TAK1) and NF-κB p65 in the kidney and lung tissues of the mice was hampered by MALT1 knockdown. In vitro experiments showed that MALT1 knockdown decreased Th1 and Th17 differentiation and phosphorylation of TAK1 and NF-κB p65 in naïve CD4⁺ T cells treated with LPS, while MALT1 overexpression had the opposite effects. The effects of MALT1 knockdown and overexpression on Th1 and Th17 cell differentiation were hampered by PMA and BAY treatment, respectively. MALT1 knockdown alleviates LPS-induced multiorgan injury and inflammation probably through inhibiting the TAK1/NF-κB signaling pathway-mediated Th1 and Th17 differentiation.

Neutrophil extracellular traps (NETs) represent a critical immune defense mechanism that can become pathological in sterile inflammation. Mitochondrial damage-associated molecular patterns (mtDAMPs) emerge as particularly potent triggers of NET formation due to their bacterial-like molecular features inherited from endosymbiotic origins. This review examines the mechanisms by which key mtDAMPs, including mitochondrial DNA, ATP, cardiolipin, cytochrome c, succinate, heme and formylated peptides, induce NETosis through pattern recognition receptors typically reserved for pathogen detection. We describe the complex signaling networks downstream of mtDAMP recognition, highlighting the roles of membrane and intracellular receptors and mitogen-activated protein kinase pathways in orchestrating mtDAMP-induced NET formation. The clinical relevance of mtDAMP-induced NETosis is explored across trauma and wound healing contexts, where neutrophil phenotype along with concentration-dependent and temporal dynamics determine beneficial versus pathological outcomes. Current therapeutic approaches modulating NET formation are discussed challenges in stimulus specificity, pathway redundancy, and use of analgesics and anti-inflammatory drugs. We conclude with future research priorities that include establishing clinically relevant concentration thresholds, elucidating synergistic mtDAMP effects, and developing targeted therapeutic strategies for NET-mediated pathology in sterile inflammatory conditions.

Oral lichen planus (OLP) is a chronic T-cell-mediated immune inflammatory disease with unclear etiology. γδ T cells are crucial for regulating T-cell activity and immune inflammatory responses. The cGAS-STING-TBK1 pathway serves as an immune sentinel for cytosolic DNA that triggers proinflammatory cytokines production and T-cell recruitment. We recently verified the co-localization of STING with γδ T cells in OLP lesions. However, the molecular mechanisms governing the roles of γδ T cells in OLP remain unknown. In the present study, we firstly investigated γδ T cells subsets and functions and found that γδ T cells were enriched in OLP lesions but reduced in peripheral blood of OLP, with the Vδ1 subset predominating. Besides, proinflammatory cytokines IL-6, IL-17, and IFN-γ secreted by OLP γδ T cells were upregulated. cfDNA levels were elevated in OLP plasma, and transfection of cfDNA into primary γδ T cells activated the cGAS-STING-TBK1 pathway, enhancing cytokine secretion, which could be reversed by the STING inhibitor H-151. Furthermore, cfDNA-OLP reduced the apoptosis rate of γδ T cells and altered their differentiation into Th17 and Foxp3⁺ Treg cells. An in vivo model further validated the proinflammatory role of the STING pathway in OLP. Collectively, this study revealed distinct expression pattern of γδ T cells in OLP. Aberrant accumulation of OLP circulating cfDNA triggered the activation of cGAS-STING-TBK1 pathway, modulating γδ T cell survival, differentiation, and proinflammatory responses, thereby promoting the inflammatory responses in OLP.

Acute kidney injury-induced acute lung injury (AKI-ALI) is a severe clinical syndrome characterized by systemic inflammation, oxidative stress, and immune cell activation. Vascular non-inflammatory molecule-1 (Vanin-1, VNN1), a pantetheinase enzyme involved in oxidative stress and inflammation, has been implicated in various inflammatory diseases. However, its role in AKI-ALI and its therapeutic potential remain unclear. An AKI-ALI model was established via bilateral kidney ischemia-reperfusion (KIR) in mice. VNN1^-/- mice and pharmacological inhibition of Vanin-1 with RR6 were used to evaluate its role in AKI-ALI. Lung injury, oxidative stress, and inflammation were assessed using histological analysis, biochemical assays, and proteomic profiling. Neutrophil extracellular traps (NETs) formation was evaluated in vitro using immunofluorescence and ELISA. KIR-induced AKI resulted in severe lung injury, characterized by impaired oxygenation, increased broncho-alveolar lavage fluid protein leakage, and elevated inflammatory cytokines. Vanin-1 knockout significantly alleviated lung injury, reduced oxidative stress, and suppressed inflammation, without affecting renal injury. Proteomic and bioinformatics analyses revealed the pivotal role of neutrophils and their associated inflammatory responses during AKI-ALI. In vitro, Vanin-1 stimulation enhanced neutrophil activation and NETs formation. Pharmacological inhibition of Vanin-1 with RR6 significantly improved oxygenation, reduced lung injury, and attenuated oxidative stress and inflammation in AKI-ALI mice. Vanin-1 contributes to AKI-ALI progression by promoting NETs formation, oxidative stress, and inflammation. Both genetic deletion and pharmacological inhibition of Vanin-1 effectively alleviated lung injury, highlighting Vanin-1 as a promising therapeutic target for AKI-ALI.

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.