Journal of Leukocyte Biology最新文献

Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation. The ferroptosis mechanism involves complex interactions between fatty acid metabolism, iron metabolism, lipid peroxidation, and antioxidative defense mechanisms. Fatty acids, especially polyunsaturated fatty acids (PUFAs), are susceptible to peroxidation, leading to the formation of lipid peroxides. Iron metabolism plays a critical role, as excessive free iron catalyzes the production of reactive oxygen species (ROS) via the Fenton reaction, further promoting lipid peroxidation. Antioxidative mechanisms, including glutathione peroxidase 4 (GPX4) and other components of the glutathione system, are crucial for neutralizing lipid peroxides and preventing ferroptosis. Recent studies have highlighted the role of ferroptosis in neutrophils, particularly under pathological conditions. Neutrophils, due to their high iron content and abundance of PUFAs, are inherently predisposed to ferroptosis. Recent studies indicates that polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs) and tumor-infiltrating neutrophils (TINs) exhibit high susceptibility to ferroptosis due to dysregulated antioxidant defense mechanism through hypoxia-mediated downregulation of GPX4. Conversely, TINs resist ferroptosis through nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant pathway. Moreover, neutrophils induce ferroptosis in various cell types, such as endothelial cells, smooth muscle cells, and cardiomyocytes, through the release of neutrophil extracellular traps (NETs). This NET-mediated ferroptosis contributes to the pathogenesis of conditions such as intestinal ischemia-reperfusion injury, aortic aneurysm, acute lung injury, and doxorubicin-induced cardiotoxicity. This review consolidates current knowledge on the mechanisms of ferroptosis in neutrophils and its implications in disease progression and immune regulation. Understanding these processes may provide new therapeutic targets for modulating immune responses and improving outcomes in ferroptosis-related diseases.

Preterm neonates die at a significantly higher rate from sepsis than full-term neonates, attributable to their dysregulated immune response. In addition to tissue destruction caused directly by bacterial invasion, an overwhelming cytokine response by the immune cells to bacterial antigens also results in collateral damage. Sepsis leads to decreased gene expression of a critical transcription factor, Krüppel-like factor-2 (KLF2), a tonic repressor of myeloid cell activation. Using a murine model of myeloid-Klf2 deletion, we show that loss of KLF2 is associated with decreased survival after endotoxemia in a developmentally dependent manner, with increased mortality at postnatal day 4 (P4) compared to P12 pups. This survival is significantly increased by neutrophil depletion. P4 knockout pups have increased pro-inflammatory cytokine levels after endotoxemia compared to P4 controls or P12 pups, with significantly increased levels of IL-1β, a product of the activation of the NLRP3 inflammasome complex. Loss of myeloid-KLF2 at an earlier postnatal age leads to a greater increase in NLRP3 priming and activation and greater IL-1β release by BMNs. Inhibition of NLRP3 inflammasome activation by MCC950 significantly increased survival after endotoxemia in P4 pups. Transcriptomic analysis of bone marrow neutrophils showed that loss of myeloid-KLF2 is associated with gene enrichment of pro-inflammatory pathways in a developmentally dependent manner. These data suggest that targeting KLF2 could be a novel strategy to decrease the pro-inflammatory cytokine storm in neonatal sepsis and improve survival in neonates with sepsis.

Background: Delayed cerebral ischemia (DCI) is a significant complication of aneurysmal subarachnoid hemorrhage (aSAH). This study profiled immune responses after aSAH and evaluated their association with DCI onset.

Methods: Twelve aSAH patients were enrolled. Leukocyte populations and cytokine levels were analyzed in cerebrospinal fluid (CSF) and peripheral blood (PB) on days 3, 5, 7, 10, and 14 post-aSAH. Peripheral blood mononuclear cells (PBMCs) were collected and their cytokine production quantified following stimulation.

Results: Mixed-effects models reveal distinct immune cell dynamics in CSF compared to blood. Monocyte/macrophage numbers continue to increase in both CSF and PBMCs for days post-aSAH. CD4+ HLA (human leukocyte antigen) II+ T cells and CD8+ CD154+ T Cells increased in circulation over time. Unstimulated PBMCs showed increased IL-1β, IL-6, and TNFα production, peaking at 7 days post-aSAH, coinciding with typical DCI onset. Ex vivo stimulation of PBMCs showed that only IL-6 significantly changed over time. In CSF, cytokines peaked 5 days post-injury, preceding immune cell profile alterations.

Conclusions: Our findings reveal a time-dependent immune response following aSAH, with distinct within-patient patterns in CSF and PB. The early CSF cytokine peak preceding immune cell changes suggests a potential mechanistic link and identifies the cytokine response as a potential therapeutic target. This cytokine surge may drive immune cell expansion and prime PBMCs for increased inflammatory activity, potentially contributing to DCI risk. Future studies should explore the importance and sources of specific cytokines in driving immune activation. These insights may inform the development of targeted immunomodulatory strategies for preventing or managing DCI in aSAH patients.

Immune memory is a hallmark of the adaptive immune system. However, recent research reveals that innate immune cells also retain memory of prior pathogen exposure that prompts enhanced responses to subsequent infections. This phenomenon is termed "innate immune memory" or "trained immunity." Notably, remodeling of cellular metabolism, which closely links to epigenetic reprogramming, is a prominent feature of innate immune memory. Adaptations in glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), glutaminolysis, and lipid synthesis pathways are critical for establishing innate immune memory. This review provides an overview of the current understanding of how metabolic adaptations drive innate immune memory. This understanding is fundamental to understanding innate immune system functions and advancing therapies against infectious diseases.

Dendritic cells (DCs) play a pivotal role in orchestrating adaptive immunity in response to environmental cues such as prostaglandin E2 (PGE2). Tumors are known to establish a microenvironment rich in PGE2. Tumor-derived PGE2 is regarded as mediator of regulatory features in DCs, facilitating immune evasion and tumor progression. In DCs, the effects of PGE2 are mediated through the E-prostanoid receptor type 2 (EP2) and EP4. While the immunomodulatory effects of PGE2 signaling via EP2/4 in monocyte-derived DCs (moDCs) is well-established, its role in human blood plasmacytoid DCs (pDCs) is poorly characterized. Therefore, in this study we investigated the effect of EP2 and EP4 signaling on pDC function, as well as the relevance of modulating these receptors in pDCs exposed to tumor-derived PGE2. Our findings reveal that EP2 and EP4 exhibit distinct functions in pDCs. PGE2-EP4 signaling mediates the upregulation of maturation markers (e.g., CD83 and HLA-DR), enhances a CCR7-based migratory function, impairs the production of pro-inflammatory mediators (e.g., IFNα and CXCL9) and stimulates the expansion of CD8 T cells with a marked suppressive phenotype. In contrast, PGE2-EP2 signaling hinders the upregulation of maturation markers and induces the expansion of CD8 T cells with a suppressive character. Additionally, using different in vitro tumor models, we show that EP2/4 blockade modulates the phenotype of pDCs exposed to tumor-derived PGE2. Together, these results identify the distinctive role of EP2 and EP4 signaling in pDCs and illustrate the potential therapeutic benefit of targeting this signaling axis to mitigate tumor-induced pDC dysfunction.

In the early COVID-19 pandemic, the strain on healthcare facilities highlighted the need for reliable biomarkers to predict progression to severe COVID-19. Neutrophils, the most abundant leukocytes in circulation, are early defenders against pathogens. In a Singaporean adult cohort, early neutrophil mediators were assessed for their suitability as prognostic biomarkers of COVID-19 complications. Plasma levels of myeloperoxidase, elastase, soluble urokinase plasminogen activator receptor (suPAR) and soluble suppressor of tumorigenicity 2 (sST2) in 35 non-severe and 14 severe cases were measured twice, 2-7 days apart after hospitalisation. Nineteen controls were included. The levels of MPO, elastase, suPAR and sST2 were significantly higher in patients with severe COVID-19 compared to those with mild and healthy controls. At baseline sampling, MPO and suPAR predicted severe COVID-19 and had AUROCs of 0.76 and 0.87, respectively. MPO and suPAR at cut-off values of 26.41 ng/ml and 3.19 ng/ml, respectively showed approximately 71% sensitivity and 81 - 84% specificity to differentiate severe COVID-19. In contrast, elastase and neutrophil counts were less predictive of severe disease. In adult COVID-19, MPO and suPAR may be reliable prognostic biomarkers of severe disease during acute COVID-19. Further validation of these markers in a larger cohort and in other infectious diseases is warranted.

Enhancement of antibody-dependent cellular cytotoxicity (ADCC) is a promising adjunct approach to achieve HIV control in the absence of antiretroviral therapy but requires the development of potent ADCC-eliciting antibodies which can recognise diverse HIV-infected cell types. A panel of broadly neutralising antibodies (bNAbs) targeting HIV envelope were identified which specifically bind both HIV-infected CD4+ T cells and monocyte-derived macrophages (MDM). Afucosylated versions of these bNAbs containing ≈30% less core fucose were generated and elicited a significant increase in ADCC responses from NK cells against HIV-infected T cell and MDM targets. Afucosylation did not alter virus neutralisation or cell-binding activity of these bNAbs. Afucosylation modifications of bNAb Fc regions is thus a promising strategy to enhance Fc-mediated activity against both T cell and macrophage targets in vivo which may be employed to heighten the therapeutic potential of antibody-based immunotherapy approaches for drug-free HIV control.

Age is an important risk factor for cardiovascular diseases (CVD) and associated with a systemic, low-grade inflammation, so called "inflammaging". We aimed to investigate the impact of age and sex on the inflammatory markers S100A9 and components of the NLRP3 inflammasome at an early stage in the aging process, using mature adult and middle-aged/perimenopausal mice. Given the importance of the cardiosplenic axis in heart failure, the spleen was analyzed in addition to the left ventricle and cardiac fibroblasts. Using immunohistochemistry, flow cytometry and gene expression analysis, our study demonstrates a higher inflammatory state of the spleen in perimenopausal versus age-matched males and 3-months old female mice, whereas aging is associated with higher left ventricular gene expression of S100A9 and NLRP3 inflammasome components independent of sex. In conclusion, our data indicate that inflammatory signatures in the spleen and left ventricle already differ in middle-aged mice and are partly sex-dependent.

Immune therapy using checkpoint inhibitors or adoptive cell transfer has revolutionized the treatment of several types of cancers. However, response to treatment is currently limited to a fraction of patients. Elucidation of immune modulatory mechanisms might optimize patient selection and present ways to modify anti-cancer immune responses. We recently discovered the expression and an important costimulatory role of TAM receptor MerTK signaling on activated human primary CD8+ T cells. Here we extend our study of the costimulatory role of MerTK expression in human CD8+ T cells. We uncover a clear link between MerTK expression and less differentiated Central Memory T cells based on an increased expression of CCR7, CD45RO, CD28, CD62L, and an altered metabolic profile. In addition, we observe an improved proliferative capacity and elevated expression of effector molecule IFNγ upon recall responses of MerTK-expressing cells in vitro. Finally, using gp100TCR-transduced T cells, we demonstrate how PROS1 treatment results in improved cytotoxicity and killing of tumors. Our findings describe a role of MerTK expression in T cells, which could be exploited in the search for improving immunotherapeutic approaches.