Inflammation最新文献

Tofacitinib, an oral pan-Janus kinase (JAK) inhibitor, induces rapid remission in ulcerative colitis (UC), but only ~60% of patients respond, highlighting the need for biomarkers to guide therapy. NLRP12, a NOD-like receptor, negatively regulates inflammation by restraining NF-κB signaling and modulating microbiota-host interactions. We hypothesized that NLRP12 deficiency skews macrophage polarization toward an M1-biased state dependent on JAK-STAT signaling, thereby enhancing responsiveness to JAK inhibition. Acute colitis was induced by Dextran Sodium Sulfate (DSS) in wild-type and Nlrp12^⁻/⁻ mice. Disease severity was assessed by body weight, disease activity index, colon length, and histopathology. Tofacitinib (10 mg/kg) was administered orally from day 3 to 7. Macrophage infiltration and polarization (CD86⁺ M1, CD206⁺ M2) were assessed by flow cytometry, and STAT1 activation was measured in colon tissue and lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs) by Western blot. Nlrp12^⁻/⁻ mice exhibited more severe DSS colitis, with elevated p-STAT1 levels, enhanced CD86⁺ M1 polarization, and reduced CD206⁺ M2 populations. Tofacitinib markedly ameliorated colitis in both genotypes but conferred greater benefit in Nlrp12^⁻/⁻ mice, restoring weight, reducing histological damage, and selectively suppressing CD86⁺ M1 macrophages. In vitro, tofacitinib partially reversed the heightened STAT1 phosphorylation and M1 polarization in Nlrp12^⁻/⁻ BMDMs. NLRP12 deficiency enhances macrophage JAK-STAT1 activation, increasing sensitivity to tofacitinib due to a proinflammatory M1-dominant state. This suggests that a high M1/M2 ratio and elevated p-STAT1 could guide JAK inhibitor therapy in UC, though their predictive value requires human validation. Targeting NLRP12 or macrophage polarization may optimize treatment outcomes.

The gradual decline of endothelial function and the intensification of inflammatory responses form the basis for the occurrence and development of age-related diseases such as atherosclerosis (AS). Mitochondrial dysfunction-manifested by excessive reactive oxygen species (ROS) production, reduced mitochondrial membrane potential, and impaired mitophagic flux-and sterile inflammation are hallmarks of aged vasculature. We investigated whether bolstering mitochondrial quality control via the novel cell-penetrating antioxidant PEP-1-Catalase (CAT) could mitigate these key features of vascular aging. To model age-associated vascular pathology, ApoE⁻/⁻ mice were fed a high-fat diet (HFD) and treated with PEP-1-CAT. Endothelial cell function, plaque burden, and inflammation were analyzed. In vitro, human endothelial cells (HUVECs) were subjected to inflammatory stress and treated with PEP-1-CAT, with or without modulators of mitophagy. We assessed mitochondrial ROS, membrane potential, NOD-like receptor protein 3 (NLRP3) inflammasome activation, and the PINK1-Parkin pathway. PEP-1-CAT treatment significantly ameliorated atherogenesis and improved features of plaque stability in mice. It suppressed vascular oxidative stress, restored mitochondrial membrane potential, enhanced mitophagic flux, and inhibited NLRP3-driven inflammation. In endothelial cells, PEP-1-CAT attenuated mitochondrial oxidative stress and dysfunction. Crucially, it activated the PINK1-Parkin pathway to promote mitophagy, which was essential for its anti-inflammatory effects, as mitophagy inhibition abrogated the suppression of the NLRP3 inflammasome. Our findings demonstrate that targeting mitochondrial health with PEP-1-CAT alleviates hallmarks of atherosclerotic vascular pathology, including endothelial dysfunction and inflammation, by enhancing mitophagy. This strategy of restoring mitochondrial quality control presents a promising therapeutic approach to delay atherosclerotic vascular pathology.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) constitutes a clinically complex urological condition defined by the persistence of pelvic pain and chronic inflammation. Emerging evidence underscores the critical involvement of macrophage-mediated immune dysregulation, particularly the dominance of pro-inflammatory M1 macrophages, in driving CP/CPPS pathogenesis. Leonurine, a bioactive alkaloid derived from leonuri, exhibits various pharmacological properties and has been shown to regulate macrophage polarization in rheumatoid arthritis. This study aimed to evaluate leonurine's therapeutic efficacy in a murine experimental autoimmune prostatitis (EAP) model, established by subcutaneous injection of complete Freund's adjuvant-emulsified prostate antigens. Leonurine administration in EAP mice markedly reduced prostatic inflammatory responses, mitigated chronic pain, and inhibited the expression of pro-inflammatory cytokines. Likewise, leonurine decreased inducible nitric oxide synthase (iNOS) expression levels, an established marker for M1 macrophage polarization. Leonurine has been found to suppress M1 polarization and decrease the secretion of M1-related cytokines (IL-1β and TNF-α) in immortalized bone marrow-derived macrophages (iBMDMs) under in vitro conditions. Mechanistic investigations demonstrated that leonurine mediates its therapeutic effects by modulating the TLR4/NF-κB signaling pathway in both macrophages and EAP models. Molecular docking and dynamics simulations demonstrated stable binding interactions between leonurine and key proteins involved in the TLR4/NF-κB signaling cascade. As a whole, these findings verify that leonurine relieves experimental autoimmune prostatitis (EAP) by regulating M1 macrophage polarization through the TLR4/NF-κB signaling cascade.

Inflammation plays a pivotal role in neonatal lung injury and is closely associated with the pathogenesis of bronchopulmonary dysplasia (BPD) in preterm infants, although the underlying molecular mechanisms remain incompletely understood. Our study detected elevated serum levels of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in preterm neonates as early as postnatal day 1 among those who later developed moderate-to-severe BPD. In pulmonary fibroblasts, co-treatment. with IFN-γ and TNF-α significantly downregulated α-smooth muscle actin (α-SMA) and disrupted extracellular matrix (ECM) homeostasis, evidenced by reduced collagen type I alpha 1 (COL1A1), collagen type III alpha 1 (COL3A1), and elastin expression, but elevated fibronectin 1 (FN1) and matrix metalloproteinase-1. Furthermore, dual-cytokine exposure attenuated SMAD2/3 phosphorylation and nuclear translocation, while upregulating SMAD7. Parallel experiments using E19.5 fetal mouse lung explants recapitulated these changes, showing decreased COL1A1, elevated SMAD7, and BPD-like histopathological alterations, including alveolar simplification and enlarged airspaces. Mechanistically, IFN-γ and TNF-α synergistically promoted SMAD7 overexpression, which competitively bound to SMAD2/3 and suppressed TGF-β signaling, ultimately leading to ECM dysregulation. These data delineate a novel inflammatory axis impairing lung development, highlighting SMAD7 and TGF-β pathways as promising intervention targets.

Neuroinflammation, driven primarily by activated microglia, is a key contributor to neurological disorders. A promising therapeutic approach involves reprogramming microglia from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype. While vitamin D (VitD) has demonstrated immunomodulatory potential, its specific mechanisms in mitigating microglial inflammation are not fully understood. This study investigated the ability of VitD to reprogram lipopolysaccharide (LPS)-activated microglia toward an M2 phenotype and to elucidate the underlying molecular pathways. Our results demonstrated that VitD attenuated LPS-induced microglial activation and pro-inflammatory cytokine release in vivo, while simultaneously promoting M2 polarization in both in vitro and in vivo models. Mechanistically, VitD was found to transcriptionally activate the RNA demethylase FTO through specific vitamin D receptor (VDR) binding to the FTO promoter. Upregulated FTO then reduced the m⁶A methylation on Mxd1 mRNA in a YTHDF2-dependent manner, thereby enhancing Mxd1 mRNA stability and protein expression. The increased Mxd1 protein subsequently bound to and repressed the promoter of PTEN. This downregulation of PTEN activated the PI3K/AKT signaling pathway, which facilitated the nuclear translocation of PGC-1α, a master regulator of M2 polarization. Collectively, our findings reveal a novel FTO/Mxd1/PTEN/AKT/PGC-1α axis that mediates VitD-induced microglial reprogramming, presenting new potential therapeutic targets for the treatment of neuroinflammatory diseases.