Inflammation最新文献

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.

Sepsis, a severe infection, often leads to an overwhelming inflammatory response. Transfer RNA (tRNA)-derived small RNAs (tsRNAs), a emerging type of small RNAs, is crucial in various biological activities. Nevertheless, the connection between tsRNAs and sepsis is still unknown. We attempt to uncover the functions that these small RNAs play in sepsis. Our studies in humans, cells, and animal models revealed a significant downregulation of tiRNA-Glu-TTC-003 in the plasma of sepsis patients, in vitro macrophage inflammation models, and in the plasma and tissues of mice subjected to cecal ligation and puncture (CLP). Subsequent experiments revealed that the administration of tiRNA-Glu-TTC-003 agomir augmented the survival rate of CLP mice, mitigated organ damage, and attenuated inflammatory responses. In cellular experiments, we observed that overexpression of tiRNA-Glu-TTC-003 ameliorated the inflammatory state of cells and inhibited the expression of inflammation-related factors in M1 macrophages. Additionally, through target gene prediction and screening, we found that tiRNA-Glu-TTC-003 may interact with triggering receptor expressed on myeloid cells 2 (TREM2) to exert its functions. In THP-1 cells, the application of tiRNA-Glu-TTC-003 mimics resulted in an upregulation of TREM2 at both mRNA and protein levels, alongside a downregulation of Toll-like receptor 4 (TLR4) and its downstream effector, myeloid differentiation factor 88 (MyD88). In conclusion, tiRNA-Glu-TTC-003 demonstrates significant anti-inflammatory and protective effects in CLP mice and macrophage inflammation models. These findings suggest that tiRNA-Glu-TTC-003 may be a major factor in the inflammatory response of sepsis and provide a new idea for future treatment.

The transient receptor potential vanilloid 4 (TRPV4) channel has emerged as a key mediator of calcium dysregulation in acute lung injury (ALI), but its role in mitophagy-the selective autophagic clearance of dysfunctional mitochondria-and crosstalk with the Sirtuin 1(Sirt1)signaling axis remain unclear. Lipopolysaccharide (LPS) induced the upregulation of TRPV4, oxidative stress (ROS), and apoptosis in both in vivo and in vitro models. TRPV4 activation (GSK1016790A) exacerbated ALI by impairing mitophagy, as evidenced by reduced LC3/Translocase of the outer mitochondrial membrane 20 (TOMM20) co-localization and decreased PTEN induced kinase 1(PINK1)/PARK2 expression. Conversely, TRPV4 inhibition (GSK2193874) or knockout attenuated lung injury, enhanced mitophagic flux, and reduced mitochondrial damage. Mechanistically, TRPV4 inhibition upregulated Sirt1/Forkhead box O1(FoxO1) signaling, driving PINK1/PARK2-dependent mitophagy. Sirt1 inhibition abrogated these protective effects, confirming its critical role in the TRPV4-mitophagy axis. TRPV4 knockout༈Trpv4⁻/⁻༉mice exhibited reduced pulmonary inflammation, apoptosis, and improved mitochondrial ultrastructure compared to wild-type controls.TRPV4 exacerbated LPS-induced ALI by suppressing Sirt1/FoxO1-mediated mitophagy. Genetic or pharmacological inhibition of TRPV4 restored mitophagic clearance of dysfunctional mitochondria, offering a promising therapeutic strategy for septic ALI. These findings highlighted the TRPV4-Sirt1/FoxO1 axis as a novel target for improving outcomes in critical care settings.

Although simvastatin plays a crucial role in lipid management, tumor therapy and acute liver injury, its potential effects in autoimmune hepatitis (AIH) has received limited investigative attention. Our study demonstrated that in the ConA-induced AIH model, HMG-CoA reductase (HMGCR), the pharmacological target of simvastatin (SIM), was significantly upregulated in T cells, particularly in CD4⁺ T cells. Furthermore, our results showed that simvastatin treatment in ConA-induced AIH model reduced the level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and alleviated liver injury. Flow cytometric analysis revealed that simvastatin treatment promoted CD4⁺ T cell apoptosis while significantly reducing the secretion of crucial inflammatory cytokines in vivo and vitro, including IL-17A, IL-6, IFN-γ, and TNF-α. To explore the underlying mechanisms, we performed transcriptome sequencing on the CD4⁺ T cells from mice treated with or without simvastatin. RNA-sequencing analysis revealed the involvement of the calcium signaling pathway and transcription factor NFATC3 in the regulation of CD4⁺ T cells. qPCR and flow cytometry analyses further confirmed that simvastatin exerted its therapeutic effects by suppressing the calcium signaling pathway and downregulating the expression of nuclear factor of activated T cells 3 (NFATC3). Collectively, our study demonstrates that simvastatin alleviates CD4⁺ T cell inflammatory responses in AIH through calcium-dependent signaling pathway.

Sepsis-associated encephalopathy (SAE) is a frequent and devastating central nervous system complication of sepsis and portends a poor prognosis. Accumulating data implicate C-type lectin domain family 7 member A (Clec7a) in neuroinflammation and cognitive impairment, however, its specific role in SAE-linked cognitive impairment remains to be defined. Adult male mice received a single intraperitoneal injection of lipopolysaccharide (LPS, 5 mg·kg⁻¹ i.p.) to induce SAE. Four hours later, animals were treated with the Clec7a antagonist laminarin (250 mg·kg⁻¹ i.p.) once daily for three days. Cognitive performance was assessed on days 6-9 post-LPS using the open field, novel object recognition, and Y-maze tests. Hippocampal Clec7a expression was evaluated by Western blotting; microglial number and morphology, myelin integrity, and neuronal activity were assessed by immunofluorescence, Whole-Cell Recordings and transmission electron microscopy. SAE was characterized by marked upregulation of Clec7a and robust microglial activation in the CA1 region of the hippocampus. The LPS challenge increased Clec7a and CD68 expression, triggered excessive microglial phagocytosis of myelin, provoked axonal degeneration and nodal elongation, and reduced neuronal activity - as electrophysiologically demonstrated by hyperpolarized resting membrane potential(RMP), a trend toward an elevated rheobase current, and a decrease in the number of action potentials - along with decreased c-Fos⁺ cell numbers, ultimately leading to cognitive impairment. Laminarin treatment substantially attenuated microglial activation, preserved myelin architecture, restored neuronal activity (evidenced by normalized electrophysiological parameters), increased c-Fos⁺ cell numbers, and rescued cognitive impairment. Clec7a drives microglial activation, leading to aberrant myelin phagocytosis, neuronal hypoactivity, and cognitive impairment in SAE. Pharmacological inhibition of Clec7a reverses these alterations, highlighting Clec7a as a potential therapeutic target for SAE.

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.