Inflammation最新文献

Rheumatoid arthritis (RA), an autoimmune disease, is characterized by synovial hyperplasia, vascular occlusion, and bone erosion. Metrnl, a novel secreted protein linked to inflammatory immune regulation, has been implicated in RA pathogenesis, but its precise mechanisms remain undefined. This study aimed to elucidate Metrnl's role in RA progression and therapeutic potential. Proteomic analysis was employed to assess Metrnl's direct effects on RA fibroblast-like synoviocytes (RA-FLS). In vitro, LPS-induced RA-FLS were treated with Metrnl to evaluate proliferation, apoptosis, cell cycle progression, and expression of inflammatory cytokines (IL-6, IL-17, TNF-α) and angiogenic factors (PDGF, VEGF) via PPARγ signaling. Collagen-induced arthritis (CIA) mice models were established to validate therapeutic efficacy, with Micro-CT and histology quantifying joint damage and inflammation. Proteomics results indicated Metrnl's multidirectional role in coordinating vascular homeostasis and immune-inflammatory network activation. Molecular biological results showed that Metrnl suppressed proliferation, promoted apoptosis, and downregulated IL-6, IL-17, TNF-α, PDGF, and VEGF through PPARγ in LPS-induced RA-FLS cells. In CIA mice, Metrnl mitigated weight loss, reduced swollen joints, and improved behavioral scores. Micro-CT confirmed attenuated cartilage/bone destruction and joint deformities, while histology revealed diminished inflammatory infiltration. Metrnl exerts anti-inflammatory and anti-angiogenic effects in RA by modulating PPARγ signaling, highlighting its dual role in suppressing synovitis and vascular remodeling. These findings propose Metrnl as a novel therapeutic target to impede RA progression, offering insights into its pathological mechanisms. Furthermore, Metrnl mitigates bone erosion and joint deformities, underscoring its broader translational potential for treating bone-related disorders.

Ischemic stroke (IS), a multifaceted neurodegenerative disorder characterized by neuroinflammation and neuronal damage, is critically linked to the cGAS-STING pathway, a key mediator of neuroinflammatory responses during cerebral ischemia. However, the specific role of the STING agonist 2',3'-cGAMP (cGAMP) in modulating ischemic brain injury remains poorly understood. In this study, we investigated the therapeutic effects of cGAMP in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and in BV2 microglial cells subjected to oxygen-glucose deprivation/reperfusion (OGD/R). Network pharmacology analysis was further employed to predict potential molecular targets and mechanisms underlying cGAMP's action in IS. To validate these findings, TREM2-specific small interfering RNA (siRNA) was utilized to suppress TREM2 expression, enabling mechanistic exploration of cGAMP's activity. Our results demonstrate that cGAMP exerts neuroprotective effects in IS through a noncanonical STING signaling pathway. Specifically, we reveal that cGAMP enhances microglial/macrophage phagocytic function via TREM2-dependent mechanisms. These findings provide novel insights into the therapeutic potential of cGAMP in IS and identify TREM2 as a promising target for modulating neuroinflammation and neuronal recovery in ischemic stroke.

Retinal neuroinflammation is a key pathological feature of age-related macular degeneration (AMD), primarily driven by aberrant microglial cell activation. The expression and role of G-protein-coupled receptor 40 (GPR40), in AMD remain unclear. To investigate this pathology, we established a sodium iodate-induced mouse model of non-exudative AMD and performed in vitro experiments using LPS-stimulated microglial cells. The results showed that activation of the GPR40 receptor significantly promoted the polarization of microglial cells from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, effectively inhibiting neuroinflammation. Mechanistic studies revealed that GPR40 negatively regulates the ERK signaling pathway, inhibiting NLRP3 inflammasome activation and the release of pro-inflammatory cytokines such as IL-1β and TNF-α. In both in vivo and in vitro experiments, GPR40 activation protected photoreceptors by suppressing neuroinflammation caused by excessive microglial activation. In conclusion, this study reveals, for the first time, the critical role of GPR40 in regulating retinal neuroinflammation and its molecular mechanism. It highlights the potential therapeutic value of targeting the GPR40-ERK signaling axis to control the neuroinflammatory cascade and delay the progression of AMD and other retinal degenerative diseases.

Bone morphogenetic protein (BMP) signaling has multiple functions in immune cells, especially in the differentiation of T cells. Previously, we found that BMP6 can dramatically promote the IFN-γ production in Th1. However, the interactions between BMP6 and Th17 cells remain poorly characterized. The evidence implicates dysregulated Th17 cell differentiation as a pivotal mechanism in psoriatic pathogenesis, yet the therapeutic potential of BMP6 in this autoimmune disease needs to be further explored. This study aimed to evaluate the potentially beneficial role of BMP6 in the Th17-induced psoriatic models and investigate its possible mechanisms. Th17 cells were intervened with BMP6 in vitro. The differentiation of Th17 was observed through multi-platform assessment combining flow cytometry, qRT-PCR, and ELISA. Signaling pathway activation was evaluated by Western blotting. RNAseq was used to further discover the impact of BMP6 on Th17. For in vivo experiments, the psoriatic model of C57BL/6 mice was established and treated with BMP6 i.d., and the Th17 cells were evaluated by flow cytometry. BMP6 treatment suppressed Th17 differentiation via the Smad1/5/9 pathway and impaired mitochondrial metabolism of Th17. In the imiquimod-induced psoriatic murine model, pharmacological BMP6 administration significantly attenuated disease progression and downregulated pathogenic Th17 cell frequency in lesional skin. Our finding elucidates the potential mechanism underlying the inhibitory effects of BMP6 in Th17-induced autoimmune diseases and furnish a theoretical foundation for its clinical application.

HIV-1-associated neurocognitive disorders (HAND) are characterized by chronic CNS inflammation. Previous studies have shown that HIV-1 gp120 causes learning and memory deficits in mice and neuroinflammation in neurons and microglia through impaired autophagy. However, the regulation of autophagy in this context is unclear. We found that lncRNA SNHG1 is upregulated in HIV-1 gp120-induced microglial inflammation. Reducing SNHG1 levels alleviates this inflammation by increasing early autophagy protein ULK1, decreasing late autophagy protein p62, and enhancing the LC3B II/I ratio. Autophagy inhibitors 3-MA and CQ can reverse or enhance the effects of SNHG1 knockdown on microglial inflammation. The study suggests that knocking down lncRNA SNHG1 may enhance early autophagy initiation and late degradation, reducing neuroinflammation. The Wnt pathway inhibitor FH535 further improved this effect by increasing ULK1 protein and the LC3B II/I ratio. In contrast, the Sirt1 inhibitor EX527 activated the Wnt pathway, decreased the LC3B II/I ratio, and worsened neuroinflammation. Thus, lncRNA SNHG1 knockdown might regulate autophagy via the Sirt1-Wnt pathway to alleviate HIV-1 gp120-induced neuroinflammation, offering a new approach for HAND prevention and treatment.

Pemphigus is a severe autoimmune blistering disorder of skin and mucosa, which is elicited by gG autoantibodies targeting desmosomal components such as desmoglein 3 (Dsg3). Keratinocytes lose cytoarchitectural stability and reciprocal adhesion in a process called acantholysis, which manifests as blisters and erosions. It is widely accepted that keratinocytes themselves can produce inflammatory factors such as cytokines in response to mechanical stress. This suggests that stress as induced by the binding of autoantibodies to Dsg3 might initiate similar effects in keratinocytes. In this work, we evaluate the cytokine response of human epidermal keratinocytes after treatment with anti-Dsg antibodies (AK23 and human pemphigus IgG). Quantitative gene expression (qPCR) was performed to study cytokine expression induced after AK23 treatment. Activation of the signal transducer and activation of transcription (STAT) factors and the impact of Janus kinase (JAK) inhibitors in anti-Dsg antibodies-treated keratinocytes were evaluated by Western blotting and gene expression assays. Moreover, we studied the functional role of JAK inhibitors during anti-Dsg antibody-induced cell dissociation by dispase assay. Epidermal activation of STATs in pemphigus and control skin was determined by immunohistochemistry. Finally, a pemphigus lesion in a steroid-unresponsive patient was treated with topical ruxolitinib, the clinical response and epidermal STAT activation were assessed. Our investigation revealed that loss of epidermal integrity by AK23 is accompanied by increased expression of cytokines (IL6, IL19, IL24, IFNE) and anti-Dsg antibodies activate STAT1 and STAT3. Administration of JAK inhibitors in vitro and in vivo prevented anti-Dsg antibody-induced STAT activation and cell dissociation in keratinocytes.

Recent studies have highlighted the relationship between ferroptosis in type II alveolar epithelial cell (ATII cell) and acute lung injury (ALI). Solute carrier family 38 member 1 (SLC38A1) is a member of the SLC38 gene family, expressed in the lung, and plays a crucial role in cellular processes. To explore the beneficial effects of SLC38A1 on ATII cell damage in Acute lung injury (ALI) from the perspectives of ferroptosis. Acute lung injury was established by intratracheal administration of lipopolysaccharide (LPS) in C57BL/6 mice for 24 hours. SLC38A1 overexpression was attained via adeno- associated virus serotype 6 (AAV6) transfection. Primary type II alveolar epithelial cell (ATII cell) were transfected with lentiviral vectors (LV) encoding SLC38A1, DMT1, shSLC38A1, shULK1, and shHSP90. Lung damage was assessed by TUNEL staining and pathological staining. Protein expression and interactions were assessed by western blotting and immunoprecipitation. SLC38A1 overexpression alleviated LPS-induced injury and inflammation by inhibiting oxidative stress and mitochondrial dysfunction in mice and ATII cells. Further results demonstrated that SLC38A1 overexpression inhibited ferroptosis, which was derived from promoting the degradation of Divalent Metal Transporter 1 (DMT1). SLC38A1 promoted the interactions among DMT1, HSP90, HSC70 and Lamp-2a, enhanced the lysosomal translocation of DMT1, and thereby intensified the chaperone-mediated autophagy (CMA) of DMT1. DMT1 overexpression accentuated LPS-induced lung injury and ATII cells injury, but the effects were relieved by SLC38A1 overexpression. SLC38A1 promotes DMT1 degradation through CMA, thereby inhibiting ferroptosis and improving lung injury. Consequently, we propose that SLC38A1 might serve as a potential therapeutic target and early diagnostic marker for ALI.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Given the limited therapeutic options, identifying novel differentially expressed genes and therapeutic targets is crucial for DN. We performed transcriptome sequencing of kidney tissue from DN patients and applied bioinformatics analyses to identify dysregulated pathways and candidate genes. Transcriptomic analysis revealed significant enrichment of the necroptosis pathway in DN kidney tissues, with Z-DNA binding protein 1 (ZBP1) showing the most pronounced differential expression among pathway-associated genes. Clinical and pathological data were collected from DN patients to evaluate the correlation between ZBP1 expression and key indicators of renal function and injury, thereby assessing its association with DN progression. Our results indicate that ZBP1 expression was significantly upregulated in DN kidney tissues compared to normal peritumour tissue, and correlated with renal tubule injury and renal function. Functional studies demonstrated that ZBP1 knockdown attenuated necroptosis, tubular injury, inflammation, and fibrosis in both db/db mice and high glucose/advanced glycation end products (HG/AGEs)-stimulated MTECs (mouse renal tubular epithelial cells). Mechanistically, ZBP1 directly interacts with receptor interacting protein kinase 3 (RIPK3) to promote necroptotic cell death. Furthermore, we identified ETS proto-oncogene 1 (ETS1) as a transcriptional activator of ZBP1 under HG conditions. In summary, this study identifies ZBP1 as a key mediator of tubular injury, inflammation and fibrosis in DN via RIPK3-dependent necroptosis, highlighting its potential as a therapeutic target.