Inflammation Research最新文献

Background: CD4 + T cells are major reactive subpopulation for cellular and humoral immune responses following sepsis. The apoptosis of CD4 + T cells may contribute to sepsis-induced immunosuppression, and preventing the induction of endoplasmic reticulum stress (ERS) can ameliorate apoptosis of CD4 + T cells in sepsis. The mechanistic target of rapamycin (mTOR) pathway performs an essential regulatory role on ERS-apoptosis of CD4 + T cells. This study aims to elucidate the underlying mechanisms of mTOR regulation of ERS-apoptosis of CD4 + T cells.

Methods: In this study, based on the cecal ligation and puncture (CLP) model, 4-phenylbutyric acid (4-PBA), we firstly detected the percentage of ERS-apoptosis of CD4 + T cells with flow cytometry, Western blotting. Next, we observed the autophagy process and related makers with transmission electron microscopy (TEM) and Western blotting. Furthermore, we created CLP models with T cell-specific mTOR and TSC1 genetic knockout mice, and bafilomycin A1(Baf-A1), a selective inhibitor of autophagy to explore the regulatory role and underlying mechanism of mTOR on ERS-apoptosis of CD4 + T cells. With rapamycin, we proved the clinical potential of mTOR.

Results: Here we observed a considerably higher percentage of apoptotic CD4 + T cells in sepsis, and 4-PBA (an inhibitor of ERS) could alleviate not only ERS, but also the apoptosis of CD4 + T cells. As our previous work proved, deletion of mTOR decreased ERS-apoptosis of CD4 + T cells in sepsis. Furthermore, deficient autophagy, especially impaired autophagic flux was observed in sepsis. Mechanistically, we found knockdown of mTOR erased impaired autophagic flux, decreased ER stress-induced apoptosis, which could be reversed by Baf-A1. More importantly, rapamycin (inhibitor of mTOR) showed great clinical potential.

Conclusion: we proved that mTOR deletion could alleviate CD4 + T cells ERS-apoptosis by rescuing autophagy involving autophagosome -lysosome fusion. For the first time, we demonstrate the mTOR-autophagy-ERS-apoptosis axis in sepsis, enriching the targets for future discovery of new sepsis therapies.

Background: Regulation of vascular endothelial permeability is crucial for maintaining hemostasis and controlling extravasation of immune cells in response to injury or infection. A transient increase in vascular permeability is a vital response to inflammation, allowing neutrophils to invade the inflamed tissue and clear the pathogen.

Findings: The close interaction between neutrophils and the activated, inflamed endothelium, followed by leukocyte trafficking across the endothelial layer, can, however, also contribute to maladaptive vascular hyperpermeability. This increased permeability allows plasma proteins and fluid to escape into the surrounding tissue, leading to edema, a hallmark and frequent complication of many inflammatory disorders. Neutrophils also contribute to the resolution of inflammation by restricting further neutrophil recruitment through chemokine degradation, the formation of neutrophil extracellular traps (NETs), and by promoting their own apoptosis via the release of pro-apoptotic microparticles. Neutrophils, therefore, also contribute to the regulation of vascular permeability and to the restoration of tissue homeostasis in inflammatory conditions.

Implications: This review summarizes the known mechanisms by which neutrophils regulate acute and chronic vascular permeability in autoimmune and non-autoimmune inflammatory diseases, and highlights the potential translational implications. Finally, we discuss overlapping and distinct mechanisms in neutrophil trafficking and vascular permeability.

Background: Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus and the leading cause of chronic kidney disease worldwide. Among the many drivers of tubular injury, lipid accumulation and inflammation are emerging as major contributors to kidney disease progression, but the molecular link between lipid metabolism and inflammatory signaling remains to be determined.

Methods: Kidney biopsies from patients with DKD across pathologic classes were labelled for lipid droplets and analyzed by Nile Red spectroscopy. Digital spatial profiling and single-cell spatial transcriptomics were performed on samples from 14 patients representing different DKD classes. RNA scope and immunofluorescence microscopy were used for data validation and characterization.

Results: Lipid droplets (LD) were increasingly abundant in advanced stages of DKD, primarily accumulating in the proximal tubules. Single-cell spatial transcriptomics identified several genes-DUSP5, AZU1, COL9A1, HSPB1, and IGFBP7-as highly upregulated in DKD. Remarkably, IL32, which encodes a LD-associated cytokine, was highly enriched in injured proximal tubules. Immunofluorescence confirmed IL-32 localization to LDs predominantly within KIM1 positive tubules in moderate to advanced DKD. Furthermore, injured IL-32 expressing tubules were in close proximity to infiltrating neutrophils and macrophages, immune effectors of non-resolving inflammation and kidney disease progression.

Conclusion: IL-32 is a LD-associated cytokine upregulated during tubular injury that represents a potential link between lipid dysregulation, inflammation and progression in human DKD.

Objective: To determine how cutaneous palmitic acid (PA) modulates transient receptor potential vanilloid-1(TRPV1) in nociceptor and dorsal-root-ganglions (DRGs), and Mas-related G protein-coupled receptor B2 (MRGPRB2) in mast cells (MCs), and to investigate their associations with serum- and glucocorticoid-regulated kinase-1 (SGK1)/neural precursor cell expressed developmentally down regulated 4-like (NEDD4L) in atopic dermatitis (AD).

Methods: AD was induced in mice with nedd4l or sgk1 conditional knock-out(cKO) in nociceptor, mrgprb2, nedd4l, or sgk1 cKO in MCs. Intradermal PA, substance P(SP), or pan-palmitoylation inhibitor 2BP was administered. Isolated DRGs and mouse bone-marrow-derived-MCs (mBMMCs) were used.

Results: Cutaneous PA levels were increased in AD mice.PA intradermal injection promoted a TRPV1⁺ nociceptor-SP-MCs MRGPRB2-tryptase-AD axis. nedd4l cKO in nociceptor up-regulated cutaneous SP expression, which was further enhanced by PA. sgk1 cKO in nociceptor slightly reduced SP levels, which were further decreased by PA or 2BP. SP levels in mice with nedd4l or sgk1 cKO in MCs were increased by PA. In DRGs, supernatants from MC903-treated keratinocytes induced SGK1 and NEDD4L phosphorylation, TRPV1 S-palmitoylation, and SP production, all of which were up-regulated by PA; total and S-palmitoylated TRPV1 levels and SP production were increased following nedd4l knockdown, whereas they were slightly reduced following sgk1 knockdown and further decreased by PA. SP induced weak phosphorylation of SGK1 and NEDD4L in MCs. SP induced MRGPRB2 S-palmitoylation and tryptase release in wild-type, nedd4l or sgk1 knock-out MCs, and these effects were enhanced by PA; 2BP caused MRGPRB2 reduction in wild-type and sgk1 knock-out MCs.

Conclusions: The increased cutaneous PA exacerbates AD by promoting TRPV1 S-palmitoylation and SP production in nociceptor, followed by MRGPRB2 S-palmitoylation and tryptase release in MCs. S-palmitoylation promotes TRPV1 whereas inhibits MRGPRB2 reduction via lysosome when NEDD4L and its upstream SGK1 are not phosphorylated.

Background: Neutrophilic asthma is one of the main types of severe asthma. Our previous studies demonstrated that neutrophil extracellular traps (NETs) contribute to its pathological process. However, the underlying mechanisms remains unclear. This study aimed to investigate the potential mechanisms of NETs in neutrophilic asthma.

Methods: Clinical samples were collected from patients with neutrophilic asthma and healthy controls. A neutrophil-dominant asthmatic murine model was established using ovalbumin (OVA), Freund's complete adjuvant (CFA) and lipopolysaccharide (LPS). Airway inflammation and remodeling were assessed by pathological staining. The expression of EMT markers and Hedgehog (Hh)/Gli1 pathway markers were measured by Western blot, qPCR, and immunofluorescence.

Results: We found that the expression of dsDNA, one of the skeleton components of NETs, was significantly higher in the peripheral plasma of patients with neutrophilic asthma than that of healthy controls, and neutrophils in neutrophilic asthma patients were more likely to induce the production of NETs. We further demonstrated that NETs induced EMT in airway epithelial cells. Both in vivo and in vitro, we confirmed that reducing NETs formation or enhancing NETs degradation reversed EMT process, attenuated airway hyperresponsiveness (AHR) and alleviated airway inflammation in neutrophil-dominant asthmatic mouse model. We also found that the Hh/Gli1 pathway was activated during this process, and inhibition of the Hh/Gli1 pathway also reversed the EMT process of airway epithelium. Similarly, AHR and airway inflammation in neutrophil-dominant asthmatic mice were reduced.

Conclusions: We confirmed that NETs promote EMT in airway epithelium via activation the Hh/Gli1 signaling pathway, thus playing an important role in the pathogenesis of neutrophilic asthma. Targeting NETs or the Hh/Gli1 pathway may provide a promising therapeutic strategy for the treatment of severe neutrophilic asthma.

Reactive arthritis (ReA) is a postinfectious inflammatory disorder that may be difficult to treat in refractory cases. We describe a 20-year-old man with HLA-B27-positive ReA presenting with arthritis, conjunctivitis, balanitis, and psoriasiform skin lesions. Conventional therapies, including antibiotics, nonsteroidal anti-inflammatory drugs, corticosteroids, and sulfasalazine, failed to control disease activity. Treatment with upadacitinib (15 mg/day), a selective Janus kinase 1 inhibitor (JAK1), led to rapid improvement of joint, ocular, and cutaneous manifestations within three weeks. Corticosteroids were tapered and discontinued without relapse, and reduced-dose upadacitinib maintained remission for more than three months. This case highlights the potential role of JAK1 inhibition in ReA pathogenesis and suggests upadacitinib as a promising therapeutic option for refractory disease.

Objective: ANCA-associated vasculitis (AAV) is a group of rare autoimmune diseases characterized by pauci-immune necrotizing inflammation of small to medium-sized blood vessels, in which ANCAs targeting neutrophil antigens promote neutrophil activation, endothelial injury and organ damage. Although AAV follows a relapsing-remitting course, the immune landscape during remission remains poorly defined. This study investigated leukocyte alterations across AAV subtypes and examined whether plasma from ANCA-positive and ANCA-negative eosinophilic granulomatosis with polyangiitis (EGPA) patients in remission modulates peripheral blood mononuclear cell (PBMC) responses in healthy donors (HDs).

Methods: Peripheral blood was collected from 62 AAV patients in remission and 28 age- and sex-matched HDs. Leukocyte morphology was assessed via May-Grünwald Giemsa staining. Circulating cytokines and chemokines were quantified by ELISA. HD-derived PBMCs were exposed to plasma from EGPA patients, antiphospholipid-positive controls, or HDs. Cell death, metabolic activity, and cytokine production were evaluated using Trypan Blue, Annexin V/PI staining, MTT assays, and ELISA. Chemotaxis assays assessed cell migration in response to conditioned media, with or without Anakinra or CCR1 inhibitor J113863.

Results: AAV patients showed increased immature neutrophils. Plasma from ANCA-positive EGPA patients induced PBMC death, inflammasome-related cytokine release, and secretion of chemotactic and proangiogenic factors. Conditioned media enhanced immune cell migration in a cytokine-dependent manner.

Conclusion: These findings indicate persistent subclinical immune activation during AAV remission, particularly in ANCA-positive EGPA, suggesting a role for mononuclear cell-mediated inflammation in relapse risk and the potential utility of immune monitoring.

Objective: M1 macrophage activation is crucial in chronic inflammatory diseases, yet its molecular mechanism is unclear.

Results: Our study showed that hemizygous deletion of the early autophagy gene atg13 (Tg+/-ATG13) disrupts cellular autophagy, hinders mitochondrial oxidative metabolism, and increases reactive oxygen species (ROS) levels in splenic macrophages, leading to M1 polarization. After reducing the expression of the autophagy markers WDFY3 and LC3, flow cytometric analysis of M1/M2 markers (CD40, CD86, CD115, CD163, and CD206), decreasing oxygen metabolism, as evaluated by the ROS-sensor dye DCFDA, and Seahorse oxygen consumption studies revealed that ablation of the atg13 gene impairs mitochondrial function, triggering M1 polarization. Additionally, redox imbalance may impair Sirtuin-1 activity via nitrosylation, increasing the level of acetylated p65 in macrophages and contributing to the inflammatory response in M1Mφs. Additionally, ablation of the atg13 gene resulted in increased infiltration of M1Mφs into the muscle vasculature, deterioration of myelin integrity in nerve bundles, and a reduction in muscle strength following treadmill exercise.

Conclusions: Our study shows that impaired ATG13-driven autophagy increases inflammation through sirtuin-1 inactivation and NF-κB activation, suggesting a role for ATG13 in post-exertional malaise (PEM).

Background: Recent studies reveal that the interaction of Aryl Hydrocarbon Receptor (AhR) signaling activation with metabolic homeostasis may significantly affect the course of IBD, and the inhibition of AhR signaling may exacerbate IBD symptoms and disrupt epithelial barrier function. However, there is no recognition of how the AhR signaling pathway affects intestinal barrier function by influencing intestinal epithelial cell metabolism.

Methods: In this study, we constructed intestinal epithelial-specific AhR knockout mice, and performed comprehensive metabolomic and transcriptomic analyses on four groups of mice (WT mice, DSS mice, AhR^ΔIEC mice, and AhR^ΔIEC+DSS mice) in order to assess the metabolic and genomic effects of AhR signaling deletion in intestinal epithelial cells.

Results: Compared with wild-type mice, the knockout of the AhR gene caused characteristic changes mainly in lipid metabolism and amino acid metabolism disorders, including 69 metabolites and 64 genes. Under inflammatory conditions, changes including 94 metabolites and 3062 genes were observed in the DSS group compared to wild-type mice.In addition, down-regulation of 14 metabolites and up-regulation of 11 metabolites were observed in AhR^ΔIEC+DSS mice compared to DSS, with anti-inflammatory metabolites such as 13-hydroxy-4Z,7Z,10Z,14E,16Z,19Z-docosahexaenoic acid、prostaglandin i2, pg 42: 11, 1,2-distearoyl-sn-glycero-3-phospho-l-serine decreased dramatically, whereas the pro-inflammatory metabolites prosapogenin a, 12,13-dihydroxy-9z-octadecenoic acid, pro-leu, n-acetyl-l-aspartic acid increased significantly. Analysis of RNA-Seq data showed that the genetic changes caused by AhR knockdown were mainly focused on lipid metabolism, amino acid metabolism and other pathways. In addition, comprehensive metabolomic and transcriptomic analyses showed that in the correlation analysis of 25 metabolites and 30 differentially expressed genes, pro-inflammatory factor Saa1 was positively correlated with multiple pro-inflammatory metabolites such as pro-leu and pheniramine, while the anti-inflammatory factor Saa3 was positively associated with several anti-inflammatory metabolites such as prostaglandin i2, 1,2-distearoyl-sn-glycero-3-phospho-l-serine.

Conclusion: These genes and metabolites involved in metabolic dysregulation pathways may provide a more specific and reliable research direction to study the protective mechanisms of AhR on the intestinal epithelial barrier and provide new insights into the effects of AhR on regulating the metabolism of intestinal epithelial cells in the development of IBD.

Objective and design: This prospective multicenter cohort study was conducted to identify and compare clinical factors associated with the effectiveness of commonly used biologics in Chinese patients with moderate-to-severe psoriasis.

Subjects: Patients from the SPEECH registry initiating treatment with ixekizumab, secukinumab, guselkumab, or ustekinumab were included.

Treatment: Guideline-recommended dosing; 3-month follow-up.

Methods: The primary endpoint was PASI90 response at 3 months. Multivariable logistic regression estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for clinical predictors of treatment response.

Results: A total of 717 patients were included in the analysis. In guselkumab-treated patients, obesity (aOR 0.22, 95% CI 0.06-0.78) and prior biologic exposure (aOR 0.22, 95% CI 0.06-0.75) were independently associated with reduced PASI90 response. Psoriatic arthritis predicted poorer response to ustekinumab (aOR 0.16, 95% CI 0.03-0.78). For secukinumab, male sex reduced the likelihood of PASI90 (aOR 0.47, 95% CI 0.23-0.96), whereas family history of psoriasis improved outcomes (aOR 2.20, 95% CI 1.10-4.42). In ixekizumab-treated patients, obesity (aOR 0.38, 95% CI 0.18-0.80) was a negative predictor, while family history (aOR 2.79, 95% CI 1.22-6.38) enhanced treatment response.

Conclusions: Predictors of biologic effectiveness differ by agent, supporting personalized treatment based on patient characteristics.