Journal of Leukocyte Biology最新文献

Neutrophil KLF2 regulates inflammasome-dependent neonatal mortality from endotoxemia.

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-04-02 DOI: 10.1093/jleuko/qiaf040

Devashis Mukherjee, Sriram Satyavolu, Asha Thomas, Sarah Cioffi, Yuexin Li, E Ricky Chan, Katherine Wen, Alex Y Huang, Mukesh K Jain, George R Dubyak, Lalitha Nayak

{"title":"Neutrophil KLF2 regulates inflammasome-dependent neonatal mortality from endotoxemia.","authors":"Devashis Mukherjee, Sriram Satyavolu, Asha Thomas, Sarah Cioffi, Yuexin Li, E Ricky Chan, Katherine Wen, Alex Y Huang, Mukesh K Jain, George R Dubyak, Lalitha Nayak","doi":"10.1093/jleuko/qiaf040","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf040","url":null,"abstract":"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.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Temporal Immune Profiling in the CSF and Blood of Patients with Aneurysmal Subarachnoid Hemorrhage.

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-03-28 DOI: 10.1093/jleuko/qiaf038

Thomas A Ujas, Katie L Anderson, Jenny Lutshumba, Samantha N Hart, Jadwiga Turchan-Cholewo, Kevin W Hatton, Adam D Bachstetter, Barbara S Nikolajczyk, Ann M Stowe

{"title":"Temporal Immune Profiling in the CSF and Blood of Patients with Aneurysmal Subarachnoid Hemorrhage.","authors":"Thomas A Ujas, Katie L Anderson, Jenny Lutshumba, Samantha N Hart, Jadwiga Turchan-Cholewo, Kevin W Hatton, Adam D Bachstetter, Barbara S Nikolajczyk, Ann M Stowe","doi":"10.1093/jleuko/qiaf038","DOIUrl":"10.1093/jleuko/qiaf038","url":null,"abstract":"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.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolic Adaptations Driving Innate Immune Memory: Mechanisms and Therapeutic Implications.

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-03-26 DOI: 10.1093/jleuko/qiaf037

Dan Hao, Margaret A McBride, Julia K Bohannon, Antonio Hernandez, Benjamin Klein, David L Williams, Edward R Sherwood

引用次数: 0

Distinct roles of PGE2 signaling via EP2 and EP4 in circulating pDCs: implications for immune modulation in the tumor microenvironment.

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-03-21 DOI: 10.1093/jleuko/qiaf034

Jorge Cuenca-Escalona, Mark W D Sweep, Mark A J Gorris, Boer T Duiveman-de, Alessandra Cambi, Georgina Flórez-Grau, I Jolanda M de Vries

{"title":"Distinct roles of PGE2 signaling via EP2 and EP4 in circulating pDCs: implications for immune modulation in the tumor microenvironment.","authors":"Jorge Cuenca-Escalona, Mark W D Sweep, Mark A J Gorris, Boer T Duiveman-de, Alessandra Cambi, Georgina Flórez-Grau, I Jolanda M de Vries","doi":"10.1093/jleuko/qiaf034","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf034","url":null,"abstract":"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.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Early neutrophil responses are potential biomarkers to predict severe COVID-19 in adults.

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-03-20 DOI: 10.1093/jleuko/qiaf035

Ananya Singh, Nurhidayah Binte Mohamed Yazid, Raika Francesca Morales, Keisuke Ejima, Po Ying Chia, Siew Wai Fong, Lisa F P Ng, Laurent Renia, David Chien Lye, Lousia Jin Sun, Seow Yen Tan, Louis Yi Ann Chai, Shirin Kalimuddin, Barnaby Edward Young, Tsin Wen Yeo, Andrew Teo

{"title":"Early neutrophil responses are potential biomarkers to predict severe COVID-19 in adults.","authors":"Ananya Singh, Nurhidayah Binte Mohamed Yazid, Raika Francesca Morales, Keisuke Ejima, Po Ying Chia, Siew Wai Fong, Lisa F P Ng, Laurent Renia, David Chien Lye, Lousia Jin Sun, Seow Yen Tan, Louis Yi Ann Chai, Shirin Kalimuddin, Barnaby Edward Young, Tsin Wen Yeo, Andrew Teo","doi":"10.1093/jleuko/qiaf035","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf035","url":null,"abstract":"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.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Decoding Eosinophils: Biological insights hidden in plain sight?

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-03-18 DOI: 10.1093/jleuko/qiaf030

Julia L M Dunn, Lisa A Spencer

引用次数: 0

Afucosylated broadly neutralising antibodies targeting HIV envelope elicit enhanced NK cell-mediated cytotoxicity against HIV-infected CD4+ T cell and macrophage targets.

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-03-15 DOI: 10.1093/jleuko/qiaf033

Olivia Wilhelm, Christine Jordan, Hans Kek, Morgane M Brunton-O'Sullivan, Laura Rikard-Bell, Pradhipa Ramanathan, Amy W Chung, Pantelis Poumbourios, Bruce D Wines, Anthony Jaworowski, Anna C Hearps

{"title":"Afucosylated broadly neutralising antibodies targeting HIV envelope elicit enhanced NK cell-mediated cytotoxicity against HIV-infected CD4+ T cell and macrophage targets.","authors":"Olivia Wilhelm, Christine Jordan, Hans Kek, Morgane M Brunton-O'Sullivan, Laura Rikard-Bell, Pradhipa Ramanathan, Amy W Chung, Pantelis Poumbourios, Bruce D Wines, Anthony Jaworowski, Anna C Hearps","doi":"10.1093/jleuko/qiaf033","DOIUrl":"https://doi.org/10.1093/jleuko/qiaf033","url":null,"abstract":"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.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sex differences in age-related cardiac and splenic S100A9 and NLRP3 expression.

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-03-15 DOI: 10.1093/jleuko/qiaf031

Kathleen Pappritz, Isabel Voss, Muhammad El-Shafeey, Sophie Van Linthout

引用次数: 0

MerTK signaling in human primary T cells modulates memory potential and improves recall response. 人原代 T 细胞中的 MerTK 信号调节记忆潜能并改善回忆反应

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-03-14 DOI: 10.1093/jleuko/qiae226

Anne Rahbech, Annina Kurzay, Sara Fresnillo Saló, Tina Seremet, Reno Debets, Özcan Met, Marlies J W Peeters, Per Thor Straten

{"title":"MerTK signaling in human primary T cells modulates memory potential and improves recall response.","authors":"Anne Rahbech, Annina Kurzay, Sara Fresnillo Saló, Tina Seremet, Reno Debets, Özcan Met, Marlies J W Peeters, Per Thor Straten","doi":"10.1093/jleuko/qiae226","DOIUrl":"10.1093/jleuko/qiae226","url":null,"abstract":"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.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142467621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Glutamine modulates neutrophil recruitment and effector functions during sterile inflammation. 谷氨酰胺能调节无菌炎症期间中性粒细胞的招募和效应功能。

IF 3.6 3区医学

Journal of Leukocyte Biology Pub Date : 2025-03-14 DOI: 10.1093/jleuko/qiae243

Katharina E M Hellenthal, Katharina Thomas, Nadine Ludwig, Anika Cappenberg, Lena Schemmelmann, Tobias Tekath, Andreas Margraf, Sina Mersmann, Katharina Henke, Jan Rossaint, Alexander Zarbock, Wida Amini

{"title":"Glutamine modulates neutrophil recruitment and effector functions during sterile inflammation.","authors":"Katharina E M Hellenthal, Katharina Thomas, Nadine Ludwig, Anika Cappenberg, Lena Schemmelmann, Tobias Tekath, Andreas Margraf, Sina Mersmann, Katharina Henke, Jan Rossaint, Alexander Zarbock, Wida Amini","doi":"10.1093/jleuko/qiae243","DOIUrl":"10.1093/jleuko/qiae243","url":null,"abstract":"During sterile inflammation, tissue damage induces excessive activation and infiltration of neutrophils into tissues, where they critically contribute to organ dysfunction. Tight regulation of neutrophil migration and their effector functions is crucial to prevent overshooting immune responses. Neutrophils utilize more glutamine, the most abundant free α-amino acid in the human blood, than other leukocytes. However, under inflammatory conditions, the body's requirements exceed its ability to produce sufficient amounts of glutamine. This study investigates the impact of glutamine on neutrophil recruitment and their key effector functions. Glutamine treatment effectively reduced neutrophil activation by modulating β2-integrin activity and chemotaxis in vitro. In a murine in vivo model of sterile inflammation induced by renal ischemia-reperfusion injury, glutamine administration significantly attenuated neutrophil recruitment into injured kidneys. Transcriptomic analysis revealed, glutamine induces transcriptomic reprograming in murine neutrophils, thus improving mitochondrial functionality and glutathione metabolism. Further, glutamine influenced key neutrophil effector functions, leading to decreased production of reactive oxygen species and formation of neutrophil extracellular traps. Mechanistically, we used a transglutaminase 2 inhibitor to identify transglutaminase 2 as a downstream mediator of glutamine effects on neutrophils. In conclusion, our findings suggest that glutamine diminishes activation and recruitment of neutrophils and thus identify glutamine as a potent means to curb overshooting neutrophil responses during sterile inflammation.","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0