Journal of Leukocyte Biology最新文献

{"title":"Withania somnifera extracts and withaferin A differentially regulate neutrophil pyroptosis, NETosis, and apoptosis.","authors":"Partha Sarathi Mondal, Apurwa Singhal, Ritvik Guru, Priyanka Kothari, Tulika Chandra, Anagha Ranade, Alok Kumar Srivastava, Manoj Kumar Barthwal, Madhu Dikshit, Sachin Kumar","doi":"10.1093/jleuko/qiag049","DOIUrl":"10.1093/jleuko/qiag049","url":null,"abstract":"<p><p>Neutrophils are short-lived, yet critical components of the innate immune system. These cells play crucial roles in host defense and inflammation. Their high turnover during inflammatory responses is often accompanied by inflammatory lytic cell death, such as NETosis and pyroptosis, which can amplify tissue damage. Thus, targeting neutrophil death pathways is an emerging therapeutic area. Withania somnifera (L.) Dunal (WS), a key Ayurvedic herb, shows immunomodulatory properties, but its effects on neutrophils remain underexplored. In this study, we investigated the impact of WS extracts and their major constituents, including withanolide A (WL), withanoside IV (WT), withanone (WO), and withaferin A (WFA), on the mechanisms of neutrophil death. Our findings reveal that WS extracts significantly attenuate interleukin-1β (IL-1β) release and pyroptotic cell death, with the alcoholic extract exhibiting greater efficacy than hydro-alcoholic and aqueous preparations. These effects are linked to the inhibition of NLRP3 inflammasome activation and caspase-1 signaling. Moreover, the alcoholic extract of WS suppressed phorbol 12-myristate 13-acetate (PMA)-induced NET formation, but did not affect ionomycin-induced NETosis. This selective inhibition was associated with a reduction in reactive oxygen species (ROS) generation, but had no effect on peptidyl arginine deiminase 4 (PAD4) activity. The WS alcoholic extract also conferred protection against neutrophil apoptosis, as evidenced by the downregulation of executioner caspase-7. Further analysis specified that WFA was primarily responsible for these effects. Together, these results provide novel insights into the role of WS and WFA in modulating neutrophil death pathways. These findings further highlighted the therapeutic potential of WS in inflammatory and neutrophil-mediated pathological conditions.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":"118 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148016074","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}

{"title":"Actin regulation of neutrophil effector mechanisms in health and disease.","authors":"Noelle Pisacano, Rebecca A Evans, Abigail S Nutley, Katharine M Lodge, Maria Prendecki","doi":"10.1093/jleuko/qiaf142","DOIUrl":"10.1093/jleuko/qiaf142","url":null,"abstract":"<p><p>Neutrophils are central to immune responses in health and disease, and their ability to deform correlates with their functional responses. In health, reorganization of the neutrophil cytoskeleton allows neutrophils to carry out their effector mechanisms. However, in the disease state, dysregulation of neutrophil cytoskeletal properties results in disruption of neutrophil structural integrity, in turn altering their immune response capabilities. We outline how actin and actin polymerization are essential for cell processes, the role of actin in neutrophil function, and how disruption of actin can lead and contribute to a range of disease pathogeneses.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251307","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}

{"title":"Macrophage heterogeneity influences cellular response to HIV infection and latency modulation.","authors":"Michelle E Wong, Laura Rikard-Bell, Salimeh Ebrahimnezhaddarzi, Morgane Brunton-O'Sullivan, Betty Kouskousis, Mark Ziemann, Anthony Jaworowski, Anna C Hearps","doi":"10.1093/jleuko/qiag053","DOIUrl":"10.1093/jleuko/qiag053","url":null,"abstract":"<p><p>HIV reservoirs persist in macrophages in people with HIV despite antiretroviral therapy, representing a barrier to cure. Factors that govern the establishment and reversal of HIV latency in different macrophage types remain poorly understood. An in vitro HIV latency model was used to investigate infection in human monocyte-derived macrophages (MDM), alveolar-like MDM (AlvMDM), and monocyte-derived microglia (MDMi). HIV infection and latency reactivation were similar between MDM and AlvMDM, while MDMi showed low susceptibility to HIV infection and minimal latent infection. Polarization of MDM and AlvMDM with M2-, but not M1-, inducing cytokines enhanced HIV reactivation, while TLR stimulation inhibited HIV reactivation in latently infected AlvMDM, but not MDM. Single-cell RNA-seq analysis identified nonproductively infected macrophages expressing HIV RNA transcripts, consistent with latently infected cells. Latently infected MDM and AlvMDM exhibited upregulated expression of genes encoding cell surface receptors, including MERTK and the immune checkpoint molecule CD137, respectively. Purification of nonproductively infected AlvMDM with high CD137 expression enriched for cells with higher HIV DNA content. Substantial differences were observed between macrophage types in both the extent and nature of transcriptional changes in response to latent and productive infection, with HIV infection having a greater impact on AlvMDM as compared to MDM. These findings highlight significant differences between macrophage types regarding their susceptibility to latency modulation and response to HIV infection. Further, we identify unique transcriptional changes in latently infected, monocyte-derived macrophages which differ by macrophage type. These findings have implications for the development of strategies to target latently infected tissue macrophages for HIV elimination.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773799","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}

{"title":"Immune landscape of COVID-19 recovery: Nucleocapsid as a major target of CD8+ T cell antiviral responses in convalescent HLA-A*02+ individuals from Brazil.","authors":"Ágata Lopes-Ribeiro, Geovane Marques-Ferreira, Franklin Pereira Araujo, Patrícia de Melo Oliveira, Alice Aparecida Lourenço, Laura Cardoso Corrêa-Dias, Thaíza Aline Pereira-Santos, Caio Wilker-Teixeira, Letícia Gomes-de-Pontes, Victor de Melo Rocha, Erik Reis, Samille Henriques Pereira, Adriana Alves Oliveira Paim, Luis Adan Flores Andrade, Camila Pacheco Silveira Martins da Mata, Flávio Guimarães da Fonseca, Fernanda Daniela Santos Coelho, Rafael Pacheco Coelho, Gabriel Pacheco Coelho, Vanessa Peruhype-Magalhães, Andréa Teixeira-Carvalho, Olindo Assis Martins-Filho, Afshin Beheshti, Moriya Tsuji, Jordana Grazziela Alves Coelho-Dos-Reis","doi":"10.1093/jleuko/qiag050","DOIUrl":"10.1093/jleuko/qiag050","url":null,"abstract":"<p><p>Despite advanced knowledge on the SARS-CoV-2-induced immunity, a deeper understanding of how virus-specific responses are assembled upon infection is necessary. Therefore, the present work investigates the major histocompatibility complex-restricted virus-specific responses of acute and postacute COVID-19 patients. Our results indicate that convalescent individuals displayed and maintained higher counts of effector memory and terminally differentiated effector memory (TEMRA) CD4+ T and CD8+ T cells as compared with severe COVID-19. Mild COVID-19 displayed a higher early activation profile in memory subsets as compared with severe and convalescent individuals. Regarding the virus-specific T cell responses, SARS-CoV-2 nucleocapsid (N) protein arose as a major target of CD8+ T cells in convalescent HLA-A*02+ individuals, adding to the specific cellular response mediated by the spike (S) protein. Unsupervised analysis enabled the unbiased clustering of lymphocytes and the assessment of differential expression of CD69, production of intracellular IFN-γ, and reactivity to HLA-A*02 tetramers bearing N or S peptides. Furthermore, cell clones targeting S and N proteins of SARS-CoV-2 undergo cellular expansion in HLA-A*02+ convalescent individuals following in vitro antigenic recall by stimulation with inactivated SARS-CoV-2 and viral proteins. Convalescent from COVID-19 presents higher connectivity of the overall immune response in comparison with the acute phase, regardless of disease severity. Collectively, our data shed new light on the role of the protein N-mediated immunity against SARS-CoV-2 in patients from one of the most affected areas in Brazil.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147839016","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}

{"title":"CD177 promotes NLR inflammasome activation in acute respiratory distress syndrome by remodeling neutrophil glycolytic metabolism.","authors":"Dongfeng Shen, Yuejiao Sun, Yixin Xu, Yahong Sun, Xiaolong Ma","doi":"10.1093/jleuko/qiag051","DOIUrl":"10.1093/jleuko/qiag051","url":null,"abstract":"<p><p>Acute respiratory distress syndrome is a high-mortality lung disorder driven by excessive neutrophil activation. While neutrophils are central to acute respiratory distress syndrome, the metabolic pathways fueling their inflammatory response remain unclear. This study identifies CD177 as a critical regulator of neutrophil glycolysis and NLRP3 inflammasome activation. Bioinformatics and animal models show that elevated CD177 correlates strongly with increased lactate and interleukin-1β levels. In vitro experiments demonstrate that CD177 knockdown reduces glycolytic flux and suppresses interleukin-1β release, a process reversed by lactate supplementation. Furthermore, treating acute respiratory distress syndrome mice with anti-CD177 antibodies significantly reduces pulmonary edema and tissue injury. These results establish the CD177-glycolysis-NLRP3 axis as a major driver of lung inflammation. Targeting this metabolic checkpoint provides a promising strategy for treating acute respiratory distress syndrome.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773789","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}

{"title":"Factor H-related protein 1 deficiency and risk of severe falciparum malaria in Ghanaian children: a cohort analysis.","authors":"Alliyah Uhmon Byrd, Lucy Wahler, Thorsten Thye, Timo Reiss, Anna Bachmann, Gabriele Pradel","doi":"10.1093/jleuko/qiag063","DOIUrl":"10.1093/jleuko/qiag063","url":null,"abstract":"<p><p>Malaria caused by Plasmodium falciparum remains a leading cause of childhood mortality in sub-Saharan Africa. The intraerythrocytic parasite can evade complement-mediated destruction through recruitment of human Factor H (FH). In vitro, Factor H-related protein 1 (FHR-1) competes with FH for binding sites, suggesting a potential role in modulating complement activation during infection. Because one-third of Africans carry a CFHR3/1 deletion, we examined the impact of FHR-1 deficiency on malaria severity. We analyzed plasma from 500 Ghanaian children presenting with different clinical manifestations. One-third of plasma samples lacked detectable FHR-1 protein, but logistic regression analysis revealed no association between FHR-1 deficiency and risk of severe malaria. In contrast, FHR-1 deficiency was overrepresented among children presenting with anemia and multiple syndromes and affected children exhibited markedly lower hemoglobin levels. These findings indicate that FHR-1 deficiency does not affect overall progression of severe falciparum malaria, but correlates with severe malarial anemia.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147941685","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}

{"title":"Gut-derived, inflammatory ILC2s disseminate type 2 immunity to remote lung in food allergen-challenged mice.","authors":"Natalie A Falta, Leigha D Larsen, Kriti Gupta, Uryan I Can, Arman Kian, Jordan D Pan, Christopher M Evans, R Lee Reinhardt, Lisa A Spencer","doi":"10.1093/jleuko/qiag056","DOIUrl":"10.1093/jleuko/qiag056","url":null,"abstract":"<p><p>Dissemination of type 2 immunity along skin-gut-lung axes contributes to allergic march progressions in atopic individuals, yet the underlying mechanisms remain incompletely understood. In mice, gastrointestinal helminth infections can mobilize a circulating pool of gut-derived, inflammatory type 2 innate lymphoid cells (iILC2s), which, in turn, establish an early type 2 immune response in remote lung. Here, using the model allergen ovalbumin, we demonstrate duodenum-restricted expansion of iILC2s is similarly elicited in response to an ingested food allergen. Gut-derived iILC2s migrated to mesenteric lymph nodes and lung, wherein they positively correlated with local lung Il13 expression within 1 h of food-allergen ingestion. Duodenal iILC2 expansion was accompanied by duodenal tuft cell expansion and IL-25 production, and treatment with IL-25 recapitulated iILC2 expansion and lung migration in the absence of allergen. Inhibition of iILC2 migration attenuated the rapid food allergen- or IL-25-induced Il13 response and subsequent mucin dysregulation in remote lung. Eosinophil infiltration proceeded iILC2s into remote lungs by 24 h; however, neither pharmacologic nor genetic inhibition of iILC2s prevented food allergen- or IL-25-elicited eosinophil remote lung homing, decoupling eosinophil recruitment from iILC2s. Collectively, these data shed new light on type 2 immune dissemination along the gut-lung axis by revealing the duodenum as a regional hub for food allergen-driven expansion of iILC2s that rapidly reshape the remote lung cytokine milieu.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147941646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guidelines for single-cell RNA sequencing analysis of eosinophils.","authors":"Kristina Handler, Alessandra Gurtner, Deeksha Raju, Ignacio Gonzalez-Perez, Isabelle C Arnold","doi":"10.1093/jleuko/qiag055","DOIUrl":"10.1093/jleuko/qiag055","url":null,"abstract":"<p><p>Eosinophils are challenging to profile by single-cell RNA sequencing (scRNA-seq) approaches, due to their fragile nature and the abundance of RNases and cytotoxic enzymes stored in cytoplasmic granules, which can compromise RNA integrity upon stress. Although recent technical advances have improved eosinophil recovery, their transcriptomes remain intrinsically sparse, particularly in mature cells, resulting in low gene detection and high dropout rates that can bias standard preprocessing and quality-control steps. Here, we integrated multiple publicly available eosinophil scRNA-seq datasets and performed comparative analyses across platforms, tissues, and species. We show that eosinophils consistently display among the lowest transcriptome coverage, emphasizing the need for eosinophil-adapted analytical strategies. To enable reliable eosinophil annotation despite high dropout rates, we curated a dedicated eosinophil marker-gene panel derived from cross-dataset differential expression signatures. We further demonstrate that intron-inclusive genome alignment markedly increases eosinophil gene and transcript detection compared with exon-only alignment. Finally, we identify genotype-dependent programs: Il5-transgenic eosinophils exhibit a less mature profile, whereas wild-type eosinophils have stronger host-defense-associated signatures. Together, these results provide a practical framework for eosinophil-focused scRNA-seq analysis that improves eosinophil recovery, annotation, and biological interpretation in complex datasets.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773815","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}

{"title":"Correction to: Pre-ligand assembly domain-derived recombinant protein of TNFR2 inhibits the expansion of CD4+ Foxp3+ regulatory T cells.","authors":"","doi":"10.1093/jleuko/qiag060","DOIUrl":"https://doi.org/10.1093/jleuko/qiag060","url":null,"abstract":"","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":"118 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147930509","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}

{"title":"Macrophage and fibro-adipogenic progenitor communication in skeletal muscle regeneration: tissue homeostasis and pathogenic remodeling.","authors":"Seily Shrestha, Abbey L Politeski, Sarah A Dick","doi":"10.1093/jleuko/qiag054","DOIUrl":"10.1093/jleuko/qiag054","url":null,"abstract":"<p><p>Skeletal muscle regeneration depends on coordinated interactions between macrophages, fibro-adipogenic progenitors, and muscle stem cells. Following injury, macrophages transition from proinflammatory to anti-inflammatory phenotypes, regulating debris clearance, cytokine secretion, and the activity of fibro-adipogenic progenitors and muscle stem cells. Fibro-adipogenic progenitors transiently support muscle stem cell-mediated regeneration but, if not cleared appropriately, differentiate into fibroblasts or adipocytes, contributing to fibrosis and fatty infiltration. Dysregulated macrophage-fibro-adipogenic progenitor crosstalk drives pathological conditions, including Duchenne muscular dystrophy and age-related sarcopenia, where imbalances in cytokines and growth factors exacerbate maladaptive remodeling. Fibro-adipogenic progenitor-derived colony-stimulating factor 1 sustains macrophage survival while macrophage-derived signals, including tumor necrosis factor alpha and transforming growth factor beta, regulate fibro-adipogenic progenitor apoptosis, proliferation, and differentiation, shaping the regenerative niche. Single-cell and spatial transcriptomic approaches have revealed extensive heterogeneity among resident and infiltrating macrophages and fibro-adipogenic progenitor subsets, uncovering the molecular circuits underlying intercellular communication. Therapeutic strategies targeting cytokines and growth factors show promise in restoring balanced macrophage-fibro-adipogenic progenitor signaling, enhancing regeneration, and limiting fibrosis and fatty infiltration. Understanding the temporal dynamics of macrophage-fibro-adipogenic progenitor interactions is essential for developing interventions that preserve muscle homeostasis and counteract degenerative disease.</p>","PeriodicalId":16186,"journal":{"name":"Journal of Leukocyte Biology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13180659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}