Journal of immunology最新文献

{"title":"Inflammatory neutrophil responses and T cell activation in ART-treated SIVmac239-infected rhesus macaques.","authors":"Sallie L Fell, Sydney M Nemphos, James E Prusak, Hannah C Green, Jordyn Miller, Samuel Q Rowan, Natalie Valencia, Coty Tatum, Mary B Barnes, Carolina Allers, Sarah Scheuermann, Kelly Goff, Clara Krzykwa, Lori A Rowe, Nicholas J Maness, Matilda J Moström, Tiffany Hensley-McBain, Lara Doyle-Meyers, Amitinder Kaur, Jennifer A Manuzak","doi":"10.1093/jimmun/vkaf100","DOIUrl":"10.1093/jimmun/vkaf100","url":null,"abstract":"<p><p>Modern antiretroviral therapy (ART) regimens have revolutionized the management of human immunodeficiency virus (HIV) and transformed it from a life-threatening disease to a manageable chronic condition. Despite the durable viral suppression associated with ART adherence, people with HIV (PWH) continue to experience chronic immune activation and inflammation, which has been linked with increased risk of developing non-acquired immunodeficiency syndrome (AIDS) comorbidities, including cardiovascular disease, liver disease, or neurocognitive disorders. Importantly, the mechanisms underlying establishment and maintenance of immune activation in ART-treated PWH remain incompletely defined. Here, we used a nonhuman primate model to evaluate associations between markers of systemic immune activation and peripheral neutrophils in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs), both before and after ART. As expected, peripheral frequencies of activated CD4+ and CD8+ T cells were elevated during acute SIV infection and returned to baseline levels following ART initiation. Neutrophil dynamics were impacted during acute SIV infection, including decreased peripheral neutrophil frequencies, increased neutrophil degranulation, and the potential for increased neutrophil extracellular trap (NET) formation. Treatment with ART mitigated these inflammatory neutrophil effector functions. Finally, frequencies of HLA-DR+ CD4+ and CD8+ T cells were significantly positively correlated with frequencies of inflammatory CD62Ldim neutrophils and plasma levels of myeloperoxidase, a component of neutrophil granules. Taken together, these data indicate that neutrophil activity and systemic T cell activation are correlated during acute SIV and early ART. Our work provides insight into associations between neutrophil dynamics and immune activation during HIV/SIV in the context of ART.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"2307-2324"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275101","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":"miR-124-3p derived from plasma exosomes enhances M2 macrophage polarization to treat acute lung injury.","authors":"Jing Yang, Xiaokang Yin, Ting Zhang","doi":"10.1093/jimmun/vkaf097","DOIUrl":"10.1093/jimmun/vkaf097","url":null,"abstract":"<p><p>Acute lung injury (ALI) post-lung transplantation (LT) is a major clinical challenge. This study investigates the role of exosomal miR-124-3p in modulating macrophage polarization and ameliorating ALI. Using male C57BL/6J mice, we established a left lung orthotopic transplantation model. Transcriptomic analysis revealed that miR-124-3p was significantly downregulated in the plasma exosomes of LT mice. Functional experiments demonstrated that plasma exosomal miR-124-3p promotes M2 macrophage polarization by targeting Krüppel-like factor 6 (KLF6) and inhibiting the NF-κB pathway. Overexpression of miR-124-3p significantly reduced inflammation, enhanced lung tissue repair, and improved oxygenation indices in vivo. In vitro, exosomal miR-124-3p reduced M1 markers (iNOS, IL-1β, IL-6) and increased M2 markers (Arg1, Ym1, Fizz1) in macrophages, confirmed by flow cytometry and Western blot. Furthermore, overexpression of KLF6 reversed the therapeutic effects of miR-124-3p. This study identifies miR-124-3p as a critical regulator of macrophage polarization and ALI pathophysiology, providing a potential therapeutic target for managing ALI in lung transplant recipients.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"2281-2297"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575635","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":"Lpar5 regulates the CD8 T-cell response to persistent virus infection by altering exhaustion programming, survival, and NK receptor expression.","authors":"Marc A D'Antonio, Brian C Ware, James E DiLisio, Mary Jessamine Michaels, Jacqueline A Turner, Lauren M Habenicht, Bennett J Davenport, Thomas E Morrison, Roberta Pelanda, Laurent Gapin, Raul M Torres","doi":"10.1093/jimmun/vkaf210","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf210","url":null,"abstract":"<p><p>Persistent antigen exposure during chronic viral infection and tumor development drives CD8 T cells into an exhausted, hypofunctional state. Understanding the molecular pathways that enforce T-cell exhaustion is critical for improving current immunotherapies. Previously, we have shown the bioactive lipid lysophosphatidic acid (LPA) regulates CD8 T-cell function through LPA receptor 5 (LPAR5) signaling, including demonstrating that Lpar5-/- CD8 T cells exhibit enhanced tumor clearance in murine models of melanoma. Importantly, significantly elevated levels of LPA have been identified in individuals with different cancers and persistent viral infections such as HIV, hepatitis C virus, and hepatitis B virus. To investigate the role of Lpar5 in the differentiation and maintenance of exhausted CD8 T cells, we utilized the lymphocytic choriomeningitis virus (LCMV) infection model. In response to infection with LCMV Clone 13, but not Armstrong, one-quarter of Lpar5-/- animals succumbed to infection, and this was accompanied by an increased frequency of LCMV-specific Lpar5-/- CD8 T cells maintained in a less terminally exhausted state. Using P14 transgenic mice, we demonstrate that Lpar5 acts in a cell-intrinsic and temporal manner to regulate CD8 T-cell accumulation and exhaustion programming during Clone 13 infection. The enhanced accumulation of Lpar5-/- P14 cells during the acute phase of Clone 13 infection appears to be regulated by Lpar5-mediated changes in T-cell survival and not through trafficking or proliferation. RNA sequencing analyses and surface phenotyping show that Lpar5 likely regulates CD8 T-cell exhaustion through modulation of NK receptor expression, including the CD94/NKG2A inhibitory axis.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956984","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":"Malat1 regulates female Th2 cell cytokine expression through controlling early differentiation and response to IL-2.","authors":"Mags Gwynne, Katie A West, Stijn van Dongen, Ioannis Kourtzelis, Dawn Coverley, Sarah A Teichmann, Kylie R James, James P Hewitson, Dimitris Lagos","doi":"10.1093/jimmun/vkaf177","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf177","url":null,"abstract":"<p><p>Identifying cell intrinsic regulators of immune sexual dimorphism is critical for treatment of several immunopathologies. We show that Malat1 is required for appropriate cytokine expression in female but not male T helper 2 (Th2) cells. Malat1 deficiency impairs in vitro Th2 differentiation of naïve CD4+ T cells from female mice, characterized by transcriptome-wide effects and suppression of cytokine expression, particularly interleukin (IL)-10. Upon IL-10 receptor (IL10R) blockade a pronounced effect is also seen on IL-4 and IL-13. Mechanistically, naïve CD4+ T cells from Malat1-/- female mice demonstrate altered early activation kinetics and impaired early differentiation gene expression, including upregulation of an interferon-stimulated gene (ISG) module. This is followed by suppression of IL2Rα and IL2Rγ expression and IL-2-mediated differentiation. Mimicking the effect of Malat1 loss by maintaining early ISG expression in WT cells with interferon β treatment partially phenocopies the effects of Malat1 deficiency. A subset of the effects of Malat1 loss in female cells is also observed in male cells. However, this does not affect endpoint Th2 differentiation. Male CD4+ T cells demonstrate stronger early activation, higher ISG expression during early differentiation, maintenance of IL2Rα expression independently of Malat1, and lower sensitivity to exogenous IL-2 during late differentiation compared with female cells. In vivo, female, but not male, Malat1-/- mice demonstrate altered Th2 cytokine expression characterized by a reduction in IL-10+ Th2 cells in both lung and spleen following priming and challenge with Schistosoma mansoni eggs, a model of lung type 2 inflammation. Overall, these findings reveal Malat1 as a novel determinant of immune sexual dimorphism.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957008","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":"Enhanced affinity for the IL-2 receptor β subunit potently increases antitumor efficacy of IL-2 across various tumor models by reshaping the tumor microenvironment.","authors":"Ernesto Relova-Hernández, Ana Beatriz Díaz-Bravo, Rodrigo Pedroso, Miguel Ángel Gonzalez-Cruz, Tania Gómez, Eliany Arias, Dayana Pérez-Martínez, Rydell Álvarez-Arzola, Janet Avellanet, Lisandra Padrón, Addys González Palomo, Luis Graça, Kalet León, Gertrudis Rojas, Tania Carmenate","doi":"10.1093/jimmun/vkaf208","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf208","url":null,"abstract":"<p><p>The main limitations of cancer treatment with high doses of recombinant interleukin 2 (IL-2) are high toxicity and the undesired expansion of regulatory T cells. The generation of IL-2 mutated variants (muteins) with changes in the affinity for different chains of the IL-2 receptor (IL-2R) allows selective stimulation of effector cells while overcoming its toxicity. As increasing the IL-2 affinity for the IL-2R beta chain leads to better antitumor effect, we generated a group of these muteins using phage display technology, in a previous work. Recombinant Fc-fusion proteins, including these variants, resulted in improved developability properties and better in vivo effect than variants containing the IL-2 (IL-2Fc). Here, we assessed one such improved mutein, named superbeta 834 (SB834Fc), and performed a comprehensive characterization of its properties. This mutein showed a stronger antitumor effect than IL-2Fc in 5 murine tumor models: 3LL-D122, B16F10, CT26, MC38, and 4T1 at very low doses. Different from other IL-2 variants, SB834Fc, as single therapy, shows antitumor effect in a therapeutic injection scheme. This antitumor effect was coincident with strong stimulation of effector T cells in the spleen and in the tumor microenvironment, far above that observed with IL-2Fc, despite maintaining the same level of Treg stimulation. Additionally, induction of proliferation was demonstrated in CD8+ T cells isolated from human healthy donors, highlighting its translational value. These results support the SB834Fc fusion protein as a suitable candidate to develop a new cancer immunotherapy based in IL-2.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957070","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":"The ability of memory CD8 T cell subsets to numerically and functionally recover following whole body irradiation is influenced by their history of cognate antigen exposures.","authors":"Elizabeth A Escue, Mohammad Heidarian, Shravan Kumar Kannan, Mahil Rao, Sahaana Arumugam, John T Harty, Vladimir P Badovinac","doi":"10.1093/jimmun/vkaf194","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf194","url":null,"abstract":"<p><p>As a result of the growing use of nuclear energy and radiation in medical interventions within the last decade, the potential for radiation exposure among the general public has increased. Exposure to high doses of radiation severely impairs the immune system, including CD8 T cells. While the effects on the naïve and primary memory (1M) CD8 T cell pools have been partially characterized, the effect of radiation exposure on CD8 T cell memory generated after repeated antigen (Ag) exposures has not. Here, we utilized a series of adoptive transfers to generate chimeric mice containing Thy1 distinct 1M and quaternary memory (4M) P14 CD8 T cells within the same host. We found that 1M and 4M were equally susceptible to radiation-induced cell death early after irradiation. In addition, both cell types showed diminished Ag-driven cytokine production and ability to proliferate upon cognate Ag restimulation in vivo. Despite evidence that 1M and 4M attempt cell cycling in response to the lymphopenic environment, neither group numerically recovers with time. Irradiated 1M and 4M showed decreased expression of key homeostatic cytokine receptors, though expression levels of CD122/CD127 are further diminished in 4M. This, in turn, leads to changes in the composition of the memory CD8 T cell compartment in which the representation of memory CD8 T cells with history of repeated Ag stimulations is further reduced. Thus, numerical and functional recovery of memory CD8 T cells generated after repeated infections/vaccinations in radiation survivors is severely impaired, potentially leaving the host with increased susceptibility to reinfection(s).</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956999","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":"ACLY promotes NK cell effector function by regulating glycolysis and histone acetylation.","authors":"Hyogon Sohn, Ana Kolicheski, Jennifer Poursine-Laurent, Jennifer Tran, Yongjun Wang, Kelly Gan, Joshua M Tobin, Nermina Saucier, Todd A Fehniger, Jacqueline E Payton, Megan A Cooper","doi":"10.1093/jimmun/vkaf209","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf209","url":null,"abstract":"<p><p>Natural killer (NK) cells are innate immune lymphocytes important for host viral and tumor immunity. We investigated the requirement for ATP citrate lyase (ACLY) in NK cell function using an inducible genetic mouse model. ACLY regulates the citrate-malate shuttle, generating cytosolic acetyl-coenzyme A that is primarily used for acetylation or lipid synthesis. ACLY-deficient NK cells upon IL-15 activation exhibited significant defects in glycolysis, proliferation, cytokine production, and cytotoxicity, without decreased intracellular lipids. Notably, ACLY deficiency specifically resulted in reduced NK cell responses to activating receptors associated with the adapter proteins DAP10 or DAP12. This is due to decreased DAP12 and increased DAP10 transcript and protein, coupled with epigenetic profiling that demonstrated altered histone acetylation of these genes in ACLY KO. Supplementation of ACLY-deficient NK cells with acetate was sufficient to overcome most functional defects, including restoring DAP10/12 expression and activating receptor function, emphasizing the importance of ACLY-generated cytosolic acetyl-coenzyme A for NK effector functions.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12380160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957001","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":"CD20+ natural killer cells are polyfunctional, memory-like cells that are enriched in inflammatory disorders.","authors":"Özgür Albayrak, Ergün Tiryaki, Nazan Akkaya, Ali Burak Kızılırmak, Tansu Doran, Gökçe Gökmenoğlu, Muhammed Yüksel, Bürge Ulukan, Mina Üzülmez, Işıl Baytekin, Önder Kemal Soylu, Güneş Esendağlı, Ingrid Meinl, Mesrure Köseoğlu, Burcu Yüksel, Suat Erus, Çiğdem Arıkan, Seçil Vural, Müjdat Zeybel, Aysun Soysal, Edgar Meinl, Atay Vural","doi":"10.1093/jimmun/vkaf205","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf205","url":null,"abstract":"<p><p>While CD20 was initially characterized as a B cell-specific marker, its expression on memory T cells has expanded our understanding of this molecule's distribution and function. Here, we identify a previously unrecognized CD20-expressing NK cell population and demonstrate its functional significance. CD56+CD20+ NK cells exhibit hallmarks of cellular activation, including elevated NKp46, CD69, and CD137 expression, enhanced proliferative capacity, and increased production of inflammatory cytokines (IFN-γ, GM-CSF, TNF-α, IL-10). Functional analyses revealed enhanced cytotoxicity against K562 targets, correlating with increased expression of cytolytic mediators including granzymes A, B, and K, perforin, FASL, and TRAIL. Single-cell transcriptional profiling demonstrated that MS4A1-expressing NK cells possess a distinct molecular signature characterized by elevated granzyme K expression and memory-like features. These cells preferentially localize to secondary lymphoid organs and accumulate in inflammatory tissues. Notably, CD56+CD20+ NK cells are enriched in multiple inflammatory conditions, including multiple sclerosis, autoimmune hepatitis, hepatitis B infection, hepatocellular carcinoma, and lung cancer. Treatment with rituximab depletes this population, suggesting potential therapeutic implications. Our findings establish CD20+ NK cells as a functionally distinct lymphocyte subset with enhanced effector capabilities and tissue-homing properties, providing new insights into immune regulation in inflammatory diseases.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957060","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":"Harnessing CD39 inhibition to boost antitumor immunity with extracellular ATP.","authors":"Ke Jin, Rebecca Fuchs, Julie Clor, Jenna L Pappalardo, Kaustubh Parashar, Soonweng Cho, Nigel P C Walker, Matthew J Walters, Ester Fernandez-Salas, Christine E Bowman","doi":"10.1093/jimmun/vkaf187","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf187","url":null,"abstract":"<p><p>CD39 (encoded by ENTPD1) has emerged as a target for oncologic therapies. Inhibition of CD39 preserves extracellular adenosine triphosphate (eATP) and decreases extracellular adenosine (eADO) formation, thereby increasing the eATP/eADO ratio and promoting immune stimulation. RNA expression profiling of eATPases across all solid tumors in The Cancer Genome Atlas (TCGA) demonstrates that ENTPD1 has the most widespread expression. Enzymatic characterization of these eATPases shows CD39 to have the greatest catalytic activity at pH 6.8, the prevailing mildly acidic pH of the tumor microenvironment, highlighting CD39 as an ideal therapeutic target of choice for eATP preservation. In an MC38 tumor model, inhibition of CD39 led to enhanced myeloid cell activation and tumor control when combined with anti-PD-1 therapy. To better understand how the murine results would translate to a human setting in which chemotherapy is the standard of care, a human monocyte-derived dendritic cell/T cell/carcinoma cell line coculture system was developed. CD39 inhibition led to greater production of IL-2, granzyme B, and IFNγ, demonstrating that chemotherapy-induced eATP generation is sufficient to promote myeloid cell activation, resulting in enhanced T cell function. Using the coculture system, we generated the first transcriptional eATP signature developed on primary human myeloid cells and applied it to real-world datasets, illustrating a response to eATP that can be measured in human tumors. These studies provide a mechanistic rationale for CD39 inhibition to promote antitumor immunity via the enhancement of eATP-driven myeloid cell activation of T cells across a variety of tumor settings and eATP-generative modalities.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957010","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":"Associated transcription factors of allergic rhinitis: SP1 aggravates nasal epithelial barrier damage.","authors":"Zhaohui Shi, Tianfeng Zhao, Yongjin Wu, Zhiyuan Tang, Zaixing Wang, Dingbo Li, Chong Wang","doi":"10.1093/jimmun/vkaf207","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf207","url":null,"abstract":"<p><p>Allergic rhinitis (AR) is a respiratory airway disorder characterized by inflammation and barrier dysfunction. The transcription factor specificity protein 1 (SP1), a member of the Sp/Krüppel-like factor family, is known to be associated with inflammation. This study aimed to explore the impacts of SP1 on AR. An AR murine model was developed through multiple intranasal challenges with ovalbumin (OVA). Human nasal epithelial cells (HNEpCs) were cultured at the air-liquid interface (ALI) and treated with IL-13 to create a cell model with barrier damage. Bioinformation samples revealed that SP1 expression was upregulated in nasal epithelial cells of people with AR. High Sp1 expression was observed in AR mice nasal mucosa. Silencing Sp1 reduced nasal rubbing, sneezing, serum levels of IgE, histamine, and nasal swelling in AR mice. Additionally, Sp1 silencing inhibited goblet cell proliferation, eosinophilic infiltration, and levels of IL-4 and IL-13. Sp1 knockdown reversed the elevated fluorescein isothiocyanate-dextran 4 kDa permeability, nasal epithelial cell shedding, and decreased expression of E-cadherin and Claudin-1. In vitro, knocking down SP1 led to an increase in transepithelial electrical resistance and levels of E-cadherin and Claudin-1. Mechanistically, SP1 upregulated forkhead box C1 (FOXC1) expression through transcriptional activity, and FOXC1 overexpression reversed the protective effects of SP1 silencing on epithelial barrier damage. Overall, our findings suggest that SP1 aggravates AR, potentially through the transcriptional activation of SP1 to FOXC1.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957077","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}