Journal of Inflammation-London最新文献

Background: The immune system plays a pivotal role in progressing an injury through the healing cascade. However, comorbidities often lead to dysregulation of this response and are implicated in wound chronicity or stalling in the inflammatory phase, necessitating clinical intervention. The maternal-fetal interface, one of the most striking immunomodulatory microenvironments to be found in mammals, may be leveraged therapeutically in wound healing through the application of amniotic tissue allografts.

Methods: This study investigates the influence of dehydrated human amnion chorion membrane (DHACM) and lyophilized human amnion and chorion membrane (LHACM) on the inflammatory response of monocytes and macrophages in vitro. Human THP-1 monocytes and macrophages were challenged with lipopolysaccharide (LPS) or LPS + interferon gamma (INFγ), respectively, to model inflammatory conditions.

Results: LHACM and DHACM treatment significantly dampened inflammasome activity and pro-inflammatory protein production while enhancing cell survival in LPS-challenged monocytes. LPS/INFγ-challenged macrophages exhibited a phenotypic shift with treatment, synonymous with repair or regeneration functionality. This was further confirmed when these cells demonstrated corresponding attenuation of pro-inflammatory cytokine production, dampened inflammasome activity, and increased survival. Additionally, the rate of efferocytosis by DHACM and LHACM-treated macrophages was substantially elevated, indicating more efficient clearance of dead cell debris.

Conclusion: These results indicate that DHACM and LHACM modulate the pro-inflammatory response of monocytes and macrophages, while enhancing the pro-reparative functions including efferocytotic capacity and cell survival. These data are suggestive of a potential cellular mechanism by which DHACM and LHACM may facilitate an efficient and appropriate inflammatory response to support the progression through the healing cascade.

Objective: This study aimed to investigate the regulation of allergic rhinitis (AR) by methyltransferase 3 through an m6A-dependent mechanism, providing a theoretical foundation for its treatment.

Methods: An in vitro experiment was conducted in which HNEpC cells were stimulated with IL-13 (50 ng/mL) to create an AR cell model. After establishing the AR cell model, the cells were treated with DAA (m6A inhibitor) and separated into three groups: Control group, shNC group and shMETTL3 group.m6A-RIP assessed the m6A modification level of PTBP1 mRNA, while RIP was used to analyze the interaction between METTL3 and PTBP1 mRNA. On the shMETTL3 background, PTBP1 or TXNIP was re-expressed with or without the ferroptosis inhibitor ferrostatin-1 (Fer-1). Endpoints included serum cytokines/immunoglobulins (IFN-γ, IL-1β, IL-18, TGF-β, IL-4, IL-10, IgE, IgG2a, IgG1) and oxidative-stress indices (GSH, SOD, MDA) by ELISA, alongside nasal-mucosa western blots for GPX4, Nrf2, MnSOD, ACSL4, METTL3, PTBP1, and TXNIP.

Results: In vitro, shMETTL3 reduced m6A on PTBP1 mRNA and lowered PTBP1 expression. In vivo, the AR condition was associated with higher circulating IFN-γ, IL-1β, IL-18, IL-4, IL-10, IgE, IgG1, and IgG2a, together with lower TGF-β, GSH, and SOD, and a ferroptosis-prone protein profile characterized by reduced GPX4, Nrf2, and MnSOD and increased ACSL4, PTBP1, and TXNIP in nasal mucosa. Silencing METTL3 shifted these readouts toward an anti-oxidant, anti-ferroptotic state, normalizing cytokines/immunoglobulins, raising GSH and SOD while lowering MDA, and restoring a protein pattern with higher GPX4, Nrf2, and MnSOD and lower ACSL4, PTBP1, and TXNIP. Re-expression of PTBP1 or TXNIP on the shMETTL3 background attenuated these improvements and reinstated AR-like oxidative and ferroptotic features. Notably, co-administration of ferrostatin-1 with either overexpression condition re-established antioxidant capacity (higher GSH and SOD with lower MDA) and returned the Western-blot profile toward protection, consistent with a METTL3/PTBP1/TXNIP pathway that promotes ferroptotic and oxidative injury and with the capacity of pharmacologic ferroptosis blockade to counteract it.

Conclusion: Methyltransferase 3 potentially modulates ferroptosis and oxidative stress linked to AR through an m6A-dependent mechanism, thereby alleviating symptoms in AR mice.

Background: Emerging evidence suggests that renal inflammation, characterized by the activation of renal macrophages, plays a critical role in the pathogenesis of kidney diseases, including acute kidney injury (AKI). However, reliable research methods for visualizing renal macrophages remain limited. In this study, we utilized positron emission tomography (PET) imaging combined with a radiolabeled ligand targeting colony-stimulating factor 1 receptor (CSF1R) to assess the potential of CSF1R-PET as a non-invasive tool for examining renal inflammation.

Methods: Single-cell RNA sequencing analysis was performed to identify imaging biomarkers for activated macrophages in an ischemia-reperfusion (I/R)-induced AKI (I/R-AKI) model. We employed PET and in-vitro autoradiography with ¹¹C-CPPC, a CSF1R-specific radioligand, in mouse models of I/R-AKI and renal/perinephric abscesses (RA). Immunohistochemical analysis was performed to assess renal pathologies, macrophage activation, and CSF1R expression.

Results: Single-cell RNA sequencing analysis of publicly available data revealed a dramatic upregulation of CSF1R, primarily expressed in M2 macrophages, in response to I/R-AKI. PET and in-vitro autoradiography showed that retention of ¹¹C-CPPC was markedly increased in ischemic renal regions and RA-affected areas compared to normal kidney regions. Immunohistochemical analysis confirmed substantial increases in CSF1R expression and the accumulation of activated macrophages in the medullary region of I/R-AKI mice and RA-affected renal regions, supporting the in-vivo and in-vitro imaging results.

Conclusion: Our findings provide the first evidence supporting the utility of ¹¹C-CPPC-PET as a clinically-available tool for non-invasive detection of activated renal macrophages, predominantly of the M2 phenotype.

This study aimed to investigate the role of butyrate in regulating STING-induced endoplasmic reticulum stress (ERS) and CD4⁺ tissue-resident memory (TRM) T cells responses during the progression of ulcerative colitis (UC). Our results demonstrated that butyrate significantly alleviated dextran sulfate sodium (DSS)-induced colitis, as evidenced by restored intestinal epithelial architecture, reduced inflammatory cytokine, and decreased CD4⁺ TRM T cells. These protective effects were likely mediated through modulation of the STING-ERS pathway. Using a CT26 cell model, we further confirmed that STING activation promotes ERS, leading to enhanced secretion of inflammatory factors and subsequent induction of CD4⁺ TRM T cells. Importantly, butyrate effectively suppressed this STING-initiated inflammatory cascade in intestinal epithelial cells (IECs). Our findings revealed a novel mechanism by which butyrate ameliorates UC through inhibition of the STING-ERS axis in IECs, highlighting its therapeutic potential for UC treatment.

Objective: Chronic obstructive pulmonary disease (COPD) is characterized by inflammation and an immune response. However, the relationship between ferroptosis and COPD remains unknown. We aim to identify pivotal ferroptosis-related biomarkers in COPD and explore their roles in immune infiltration landscapes.

Methods: Differentially expressed genes (DEGs) were obtained from all current datasets of peripheral blood and lung tissues associated with COPD. DEGs were intersected with ferroptosis-related genes (FRGs) from FerrDb database to obtain FRDEGs. Hub FRDEGs were evaluated using WGCNA, GO, and KEGG enrichment, PPI network analysis, LASSO-COX, and ROC curve analysis, and validated in blood of COPD patients. The association between hub FRDEGs and COPD was investigated. The role of hub FRDEGs in 17 types of respiratory tract diseases was analyzed, and potential drugs targeting these FRDEGs were predicted via CMAP drug database. Importantly, MDM2 and CDKN1A expressions were identified and verified by H&E and Masson staining, and Western blot analysis in the CS and LPS-induced COPD mice.

Results: MDM2 and CDKN1A were identified as hub genes in all COPD patients, and their expressions were significantly upregulated in the lung tissues of COPD mice. 17 types of respiratory tract diseases were markedly associated with MDM2 and CDKN1A. The 2 genes were correlated with neutrophils. MDM inhibitor (AMG-232) was screened as a potentially key drug affecting MDM2.

Conclusion: MDM2 and CDKN1A could be potential targets for COPD by regulating neutrophil-involving inflammation. One drug with potential clinical application value was identified.