Inflammation最新文献

Research on spontaneous resolution of acute gout remains limited. Macrophages pyroptosis is crucial for the inflammation of acute gout, while current research mainly focus on Caspase 1/Gasdermin D axis. We aimed to investigate the involvement of other Gasdermin proteins in MSU crystal-induced macrophages, and to explore the role of Caspase 3-interacting protein alpha-1 antitrypsin (AAT) in regulating macrophage pyroptosis. Here, clinical evidence demonstrated elevated Gasdermin E (GSDME) in peripheral blood mononuclear cells (PBMCs) and CD68⁺ synovial macrophages from patients with acute gout. In THP-1-derived macrophages, activated Caspase 3/GSDME axis was found after MSU crystals stimulation, and knockdown of Caspase 3 and GSDME significantly suppressed pyroptosis. In vivo, the Caspase 3 inhibitor effectively alleviated MSU crystal-induced acute gouty arthritis in mice. Cytologically, Caspase 3 interacting protein AAT was identified using immunoprecipitation and mass spectrometry technology. Meanwhile, AAT was elevated in serum, PBMCs, synovial fluids, and CD68⁺ synovial macrophages from patients with acute gout. Furthermore, AAT inhibited Caspase 3/GSDME-dependent pyroptosis axis by binding to Caspase 3 in MSU crystal-induced macrophages. Additionally, AAT was internalized into macrophages via low-density lipoprotein receptor-related protein-1. Collectively, elevated AAT in synovial fluids from patients with acute gout attenuates macrophage pyroptosis by inhibiting Caspase 3/GSDME axis, providing a novel explanation for the spontaneous resolution of acute gout.

Acute lung injury (ALI) is a critical condition characterized by uncontrolled inflammation, respiratory insufficiency, and tissue damage, often triggered by pneumonia or sepsis. Aberrant activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and subsequent pyroptosis are key drivers of ALI pathogenesis. Palmatine (PAL), a naturally derived isoquinoline alkaloid with diverse pharmacological effects, was investigated for the therapeutic potential against lipopolysaccharide (LPS)-induced ALI in this study, focusing on NLRP3 inflammasome, pyroptosis, and metabolic regulation. Our findings showed that PAL significantly suppressed NLRP3 inflammasome activation and pyroptosis in LPS/adenosine triphosphate (ATP)-stimulated THP-1 macrophages and inhibited M1 macrophage polarization. In C57BL/6J mice subjected to intratracheal LPS challenge, PAL alleviated lung histopathological injury, decreased tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and IL-18 levels in bronchoalveolar lavage fluid, and reduced lung wet-to-dry ratio and lung tissue myeloperoxidase activity. Transcriptomic analysis revealed that PAL markedly attenuated LPS-induced upregulation of NLRP3 and Gasdermin-D (GSDMD). PAL also downregulated the mRNA expression of Caspase-1, Apoptosis-associated speck-like protein (Asc), High-mobility group box 1 (Hmgb1), Il1b, and Il18, as well as the protein levels of cleaved Caspase-1 (p20), GSDMD-N and Caspase-11 in lung tissue. Metabolomic profiling indicated PAL-driven metabolic reprogramming involving the oxidation of branched-chain fatty acids and very long-chain fatty acids. Integrated multi-omics analysis highlighted cytosolic DNA-sensing and NOD-like receptor signaling as key pathways underlying PAL's effects. Collectively, PAL mitigates ALI by inhibiting NLRP3 inflammasome activation, suppressing pyroptosis, and reprogramming metabolism, supporting its potential as a therapeutic candidate.

Allergic rhinitis (AR) is an inflammatory disease of the upper airway that primarily affects the nasal mucosa, with Th2 differentiation-driven inflammation as a key contributor. A bioinformatics analysis of dataset GSE52804 identified Six-transmembrane epithelial antigen of prostate 4 (STEAP4), a metalloreductase involved in inflammation regulation, as associated with AR progression, though its specific function remains unclear. Data obtained from nasal mucosal tissues from AR patients (n = 13) and an ovalbumin (OVA)-induced AR mouse model demonstrated a marked upregulation of STEAP4. Subsequent loss-of-function experiments revealed that STEAP4 knockdown reduced Th1/Th2 imbalance-mediated inflammation, alleviating allergic symptoms in OVA-treated mice. Further investigations involved the purification of naïve CD4⁺ T cells from healthy murine splenocytes and their Th2 polarization. Consistently, STEAP4 knockdown inhibited Th2 differentiation and the production of Th2-related cytokines in vitro. Additionally, Guanine adenine thymine adenine sequence-binding protein 3 (GATA3), a transcription factor essential for Th2 differentiation, was predicted to bind to the STEAP4 promoter. CHIP-PCR and dual-luciferase assays confirmed the transcriptional regulation of STEAP4 by GATA3. More importantly, STEAP4 knockdown rescued the promoting effects of GATA3 overexpression on Th2 differentiation. In conclusion, STEAP4 functions downstream of GATA3 to promote AR development by promoting Th2 differentiation-mediated inflammation, suggesting its potential as a target for AR treatment.

Liver fibrosis (LF) is linked to decreased type 1 interferon (IFN1) levels at steady-state, intestinal dysbacteriosis, leaky gut, and intestinal bacterial translocation. Liver leucine-rich repeats containing G protein-coupled receptor 4 (LGR4) signalling drives LF development, and intestinal LGR4 homeostasis maintains the intestinal stem cells. To explore the role of intestinal LGR4 signalling in LF and possible relationships with intrahepatic microbiota and IFN1, intraperitoneal injection of carbon tetrachloride (CCL4) was applied to induce LF in adult C57BL/6J mice with or without conditional knockout (cKO) of Lgr4 in intestinal epithelial cells (IECs). Fibrotic mice were simultaneously treated with intragastric bacteria as needed. Results showed that wild-type murine LF resulted in intestinal LGR4 reduction, increased intestinal permeability and bacterial translocation, decreased intrahepatic IFN1 levels, and decreased abundance of bacterial genera Lactobacillus, Dubosiella, and Bifidobacterium. Lgr4 cKO in IECs significantly promoted LF accompanied by increased intrahepatic abundance of genera Escherichia-Shigella, Klebsiella, Acinetobacter and decreased intrahepatic abundance of Lactobacillus, Dubosiella, and Bifidobacterium. In the absence of CCL4 challenge, Lgr4 cKO in IECs also resulted in increased intrahepatic Escherichia-Shigella and decreased Lactobacillus. In mice with Lgr4 cKO in IECs, intragastric administration of Lactobacillus significantly attenuated LF accompanied by significantly decreased intrahepatic Escherichia-Shigella, Klebsiella, and Acinetobacter along with increased intrahepatic Lactobacillus and IFN1 levels; however, deletion of the organismal IFN1 receptor abolished the Lactobacillus-mediated alleviation of LF. Co-culture of DC2.4 cells with Lactobacillus or its genomic DNA increased supernatant IFN-β levels. Overall, this study demonstrates that weakened intestinal LGR4 signalling facilitates LF by increasing intestinal permeability, altering intrahepatic microbiota composition, and decreasing liver IFN1 levels.

Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, often leads to sepsis-associated acute lung injury (SALI), a major contributor to mortality. Spermidine (SPD), a natural polyamine with anti-inflammatory and metabolic regulatory properties, has emerged as a potential nutritional adjunct for sepsis management. However, whether and how SPD ameliorates SALI remains to be elucidated. Here, cecal ligation and puncture (CLP) was performed in rats to simulate sepsis. Rat survival, lung injury score, Dry/Wet ratio, histopathology, cytokine levels and immunohistochemical analysis were analyzed to evaluate SPD's effects on SALI. Targeted metabolomics, molecular docking and cellular thermal shift assay (CETSA) identified AMP-activated protein kinase (AMPK) as an underlying target of SPD's action. In vitro investigations were based on lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs), with flow cytometry assessing apoptosis. AMPK inhibitor (Compound C) and downstream signaling were examined in vivo and in vitro through q-PCR and Western blot experiments. Consequently, SPD improved rat survival, reduced lung injury, and decreased pro-inflammatory cytokines in CLP rats. Metabolomics, molecular docking and CETSA suggested AMPK-mediated energy metabolism modulation. Mechanistically, SPD attenuated necroptosis via AMPK/RIPK1/MLKL signaling. Moreover, Compound C counteracted the protective effect of SPD on SALI in vivo and in vitro. Our findings evidence that SPD significantly ameliorates SALI via the regulation of AMPK-mediated necroptosis. SPD supplementation may serve as a complementary therapeutic approach, warranting further investigation in subsequent clinical trials for sepsis treatment.

Demyelination is a significant pathological feature of chronic cerebral ischemia. Recent evidence suggested that microglia played a protective role in mitigating brain ischemic injury via phagocytosis of myelin debris resulting from demyelination. Triggering receptor expressed on myeloid cells-like 2 (TREML2) is a newly discovered inflammation-associated transmembrane receptor expressed by microglia. To date, whether microglial TREML2 contributes to the phagocytosis of myelin debris in chronic cerebral ischemia has not been fully clarified. In this study, employing a bilateral carotid artery stenosis animal model and a CoCl₂-treated cellular model, we demonstrated for the first time that microglial TREML2 expression was upregulated in response to chronic cerebral ischemia. Utilizing Treml2-knockout mice, we provided the first evidence that Treml2 deficiency alleviated demyelination and cognitive deficits induced by chronic cerebral ischemia. Furthermore, this protective effect might be attributed to the microglial M2-type polarization and enhanced phagocytosis of myelin debris, both of which were induced by the Treml2 deficiency. Additionally, we showed that TREML2 regulated microglial phagocytosis of myelin debris via toll-like receptor 9 under ischemic conditions. These findings elucidated the mechanisms by which microglia modulated the phagocytosis of myelin debris in response to brain ischemic injury and suggested that inhibition of TREML2 might represent a novel therapeutic strategy for treating demyelination and cognitive decline induced by chronic cerebral ischemia.