Journal of Inflammation-London最新文献

Background: Sepsis is a life-threatening condition characterised by an overwhelming immune response and high fatality. While most research has focused on its acute phase, many sepsis survivors remain immunologically weakened leaving them susceptible to serious complications from even mild infections. The mechanisms underlying this prolonged immune dysregulation remain unclear, limiting effective interventions. Here, we analysed whether sepsis induced long-term "training" in hematopoietic stem and progenitor cells (HSPCs), imprinting changes that persist in their myeloid progeny.

Results: Peripheral blood analysis of 8 sepsis survivors, 12 patients with septic shock, and 10 healthy donors revealed a significant expansion of CD38 + progenitors in survivors, with increased megakaryocyte-erythroid progenitors and a near significant reduction in mature neutrophil counts. This shift suggests impaired granulopoiesis, favouring immature, immunosuppressive granulocytes. Differentiated macrophages from survivors' HSPCs exhibited impaired metabolic pathways after lipopolysaccharide stimulation, with downregulation of tricarboxylic acid cycle and glycolysis genes, indicating altered immune metabolism. Pathway analysis revealed enhanced type-I interferon (IFN) and JAK-STAT signalling in survivors' macrophages, reflective of potentially tolerance-prone reprogramming. Finally, exposing healthy donor HSPCs to IFNβ during macrophage differentiation reduced HSPC proliferation, increased apoptosis, and induced a metabolic shift towards glycolysis over mitochondrial respiration.

Conclusions: Together, these findings suggest that sepsis induces lasting reprogramming in HSPCs leading to myeloid progeny with altered immune memory that might drive immune dysregulation in survivors. These data open avenues to explore potential targets to better manage long-term immune alterations in sepsis survivors.

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.