Frontiers in Immunology最新文献

{"title":"Oxygen metabolism abnormalities and high-altitude cerebral edema.","authors":"Zhi Li, Jianping Zhang, Xiaoxia Zhang, Qiaoying Jin, Xingxing Zheng, Li Mo, Zejiao Da","doi":"10.3389/fimmu.2025.1555910","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1555910","url":null,"abstract":"<p><p>Hypobaric hypoxia is widely recognized as a prominent risk factor for high-altitude cerebral edema (HACE), which contributes to the exacerbation of multiple pathological mechanisms, including oxidative stress, mitochondrial dysfunction, disruption of blood-;brain barrier integrity, neuroinflammation, and neuronal apoptosis. Among these mechanisms, abnormalities in oxygen metabolism, including hypoxia, oxidative stress, and mitochondrial dysfunction, play pivotal roles in the pathophysiology of HACE. In this review, our objective is to enhance our comprehension of the underlying molecular mechanisms implicated in HACE by investigating the potential involvement of oxygen metabolism. Addressing aberrations in oxygen metabolism holds promise for providing innovative therapeutic strategies for managing HACE.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1555910"},"PeriodicalIF":5.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A syringeable immunotherapeutic hydrogel enhances T cell immunity via <i>in-situ</i> activation of STING pathway for advanced breast cancer postoperative therapy.","authors":"Baozhen Zhang, Min Li, Jiahua Ji, Xinghui Si, Xiaojiao Yin, Guofeng Ji, Liqun Ren, Haochen Yao","doi":"10.3389/fimmu.2025.1523436","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1523436","url":null,"abstract":"<p><p>Complete surgical resection of advanced breast cancer is highly challenging and often leaves behind microscopic tumor foci, leading to inevitable relapse. Postoperative formation of the immunosuppressive tumor microenvironment (TME) reduces the efficacy of immunotherapies against residual tumors. Although cytotoxic chemotherapeutics exert the capacity to intensify cancer immunotherapy via immunogenic cell death (ICD) effects, systemically administered chemo agents often cannot access residual tumor sites, and fail to elicit antitumor immune responses. Herein, we present a novel syringeable immunotherapeutic hydrogel (SiGel@SN38/aOX40) loaded with the DNA-targeting chemotherapeutic 7-ethyl-10-hydroxycamptothecin (SN38) and the anti-OX40 agonist antibody (aOX40). The sustained in-site release of SN38 and aOX40 activate the stimulator of interferon genes (STING) pathway, intensify type I interferons expression, synergistically facilitate dendritic cell (DC) activation, and initiate persistent T cell mediated immune responses within the surgical resection bed that eliminate residual tumors with no tumor recurrence in 120 days. Collectively, our designed SiGel@SN38/aOX40 induces robust and long-lasting tumoricidal immunity following breast cancer resection and exhibit immense potential for clinical translation.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1523436"},"PeriodicalIF":5.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oropharyngeal carcinomas induce circulating monocytes to express a TAM-like pro-tumor expression profile that suppresses T-cell proliferation.","authors":"Christopher J Papayannakos, Mohd Israr, James A DeVoti, Fung Lam, Arnon Arazi, Douglas K Frank, Dev P Kamdar, Lucio M Pereira, Nagashree Seetharamu, Bettie M Steinberg, Vincent R Bonagura","doi":"10.3389/fimmu.2025.1539780","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1539780","url":null,"abstract":"<p><strong>Introduction: </strong>Tumor-associated macrophages (TAMs) recruited from circulating monocytes drive tumor-growth and establish an immunosuppressive tumor microenvironment (TME). Initial events in transition from resting monocytes to TAMs are poorly understood. Here, we report that monocytes from oropharyngeal cancer (OPC) patients and control monocytes treated with OPC-conditioned media (CM) express a repertoire of pro-tumor mediators that is characteristic of TAMs.</p><p><strong>Methods: </strong>Monocytes were stimulated with OPC cell line CM, analyzed by single-cell RNAseq. Results of select genes were confirmed by qPCR with monocytes and analyzed in OPC tumors vs. clinically normal tissue. OPC spheroids containing control monocytes and T-cells were established, TAM phenotype characterized by flow analysis and qPCR, and T-cell proliferation assessed by flow.</p><p><strong>Results: </strong>OPC-conditioned media induced multiple pro-tumor genes including <i>CXCL1, CXCL5, CXCL8, SPP1, IL1B, GPNMB</i>, and <i>FABP5</i>. Patient monocytes had higher baseline levels or achieved higher levels after stimulation than control monocytes. A subset of patient monocytes had high baseline levels of <i>CXCL9/-10/-11</i> expression that resisted downregulation in response to stimulation, a potential sign of a more favorable TME. <i>CXCL9/-10/-11</i> expression in OPC tumor biopsies compared to clinically normal tissue correlated with patient outcome. Spheroid TAMs derived from control monocytes maintained the pro-tumor repertoire seen with monocytes stimulated by tumor line conditioned media. These TAMs suppress T-cell proliferation. Inhibition of COX-2 or IL1 signaling during differentiation into TAMs partially blocked the suppression of T-cell proliferation.</p><p><strong>Conclusion: </strong>Targeting the early transition of monocytes into pro-tumor TAMs could be used to develop new therapies for OPC.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1539780"},"PeriodicalIF":5.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in immunopathogenesis and clinical practice: mastering the challenge-managing of non-tuberculous mycobacteria.","authors":"Wiwat Chancharoenthana, Supitcha Kamolratanakul, Suwatchareeporn Rotcheewaphan, Asada Leelahavanichkul, Marcus J Schultz","doi":"10.3389/fimmu.2025.1554544","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1554544","url":null,"abstract":"<p><p>Non-tuberculous mycobacteria (NTM) are widespread environmental pathogens that can lead to significant disease burden, particularly in immunocompromised individuals, but also in those with a normal immune system. The global incidence of NTM is increasing rapidly, with <i>Mycobacterium avium</i> complex (MAC) being one of the most common types. The immunopathogenesis of the MAC involves a complex interaction between the bacteria and the host immune system. MAC survives and replicates within macrophages by preventing the fusion of phagosomes and lysosomes. The mycobacteria can neutralize reactive oxygen and nitrogen species produced by the macrophages through their own enzymes. Additionally, MAC modulates cytokine production, allowing it to suppress or regulate the immune response. Diagnosing MAC infections can be challenging, and the effectiveness of available treatments may be limited due to MAC's unpredictable resistance to various antimycobacterial drugs in different regions. Treating MAC infection requires a collaborative approach involving different healthcare professionals and ensuring patient compliance. This review aims to shed light on the complexities of MAC infection treatment, discussing the challenges of MAC infection diagnosis, pharmacological considerations, such as drug regimens, drug monitoring, drug interactions, and the crucial role of a multidisciplinary healthcare team in achieving the best possible treatment outcomes for patients.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1554544"},"PeriodicalIF":5.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Celecoxib prevents malignant progression of smoking-induced lung tumors via suppression of the COX-2/PGE₂ signaling pathway in mice.","authors":"Kaori Sakurai, Shotaro Chubachi, Jun Miyata, Junko Hamamoto, Tatsuro Naganuma, Takashi Shimada, Shiro Otake, Shingo Nakayama, Hidehiro Irie, Akihiro Tsutsumi, Naofumi Kameyama, Ahmed E Hegab, Masayuki Shimoda, Hideki Terai, Hiroyuki Yasuda, Yae Kanai, Makoto Arita, Koichi Fukunaga","doi":"10.3389/fimmu.2025.1557790","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1557790","url":null,"abstract":"<p><strong>Introduction: </strong>Lung cancer is characterized by a poor prognosis and is a significant comorbidity of chronic obstructive pulmonary disease (COPD). Therefore, effective chemopreventive agents are warranted. We evaluated the effects of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on the prevention of lung-carcinoma development using an intermittent smoking-induced lung-carcinoma mouse model. Additionally, we explored COX-2's role in lipid metabolism.</p><p><strong>Methods: </strong>Male A/J mice were exposed to sham air or mainstream cigarette smoke for 20 weeks. Vehicle or celecoxib was administered via intragastric feeding once daily. Lung tissues were analyzed for tumor nodules and emphysema; the bronchoalveolar lavage fluid was collected for cell counting. COX-2 expression was measured using real-time polymerase chain reaction and western blotting; lipidomic analysis was conducted using liquid chromatography-tandem mass spectrometry. Cell proliferation and colony-forming assays were performed on LA-4 cells to assess the effects of prostaglandins and COX-2 inhibitors.</p><p><strong>Results: </strong>Intermittent smoking exposure increased lung adenomas, adenocarcinomas, and COX-2 expression. Lung adenomas were characterized by abundant COX-2-positive cells. Celecoxib reduced intermittent smoking-induced inflammation, emphysema, and cell counts in the bronchoalveolar lavage fluid and decreased the incidence of lung adenocarcinomas, whereas the total number of observed lung tumors was unchanged. Celecoxib markedly suppressed single-smoke-induced prostaglandin E2 (PGE₂) production in the airway. PGE₂ increased LA-4 cell viability via the EP4 receptor and promoted colony formation.</p><p><strong>Discussion: </strong>Celecoxib effectively inhibited lung-carcinoma development, inflammation, and emphysema, demonstrating the potential for chemoprevention in smokers and patients with COPD. Further studies on EP4 inhibitors for the prevention of emphysema and lung cancer are warranted.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1557790"},"PeriodicalIF":5.7,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case Report: Infection with <i>Streptococcus constellatus</i> manifesting as gelatinous pleural effusion in an HIV-positive patient.","authors":"Zhongxia Yang, Wanyuan Xiong, Zibing Qian, Xiaorong Mao","doi":"10.3389/fimmu.2025.1545165","DOIUrl":"10.3389/fimmu.2025.1545165","url":null,"abstract":"<p><p><i>Streptococcus constellatus</i>, recognized as a commensal bacterium, has the potential to induce severe infections in patients with immunodeficiency. Here, we reported a rare case of <i>Streptococcus constellatus</i> infection that manifested as gelatinous pleural effusion in a patient with HIV. Although the effusion was gelatinous and partially encapsulated, it was completely resolved with timely administration of antibiotics, thereby eliminating the necessity for thoracic drainage, urokinase injection, or surgical intervention.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1545165"},"PeriodicalIF":5.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing HLA-A2-restricted CD8⁺ T-cell epitopes and immune responses to Omicron variants in SARS-CoV-2-inactivated vaccine recipients.","authors":"Chanchan Xiao, Jian Xiang, Haoyun Wang, Wen Gao, Tianchan Peng, Shumin Li, Jun Su, Xi Chen, Lijuan Gao, Ruohu Shi, Xinyi Mou, Jun Yuan, Guobing Chen","doi":"10.3389/fimmu.2025.1534530","DOIUrl":"10.3389/fimmu.2025.1534530","url":null,"abstract":"<p><strong>Introduction: </strong>Recent surveillance has identified the emergence of the SARS-CoV-2 Omicron ariant, which exhibits the ability to evade multiple neutralizing antibodies generated by prior infection or vaccination. However, significant knowledge gaps remain regarding the CD8 T-cell immune reactivity to the Omicron variant. This study aims to evaluate the characteristics of HLA-A2-restricted CD8 T-cell epitopes from the Omicron variant and analyze epitope-specific CD8 T-cell responses to SARS-CoV-2 inactivated vaccines.</p><p><strong>Methods: </strong>We conducted a comprehensive analysis of CD8 T-cell responses to SARS-CoV-2 inactivated vaccines, focusing on HLA-A2-restricted epitopes derived from the Omicron variant. Mutant epitopes were evaluated for their impact on antigen presentation and CD8 T-cell immune reactivity. Additionally, we screened for epitopes that exhibited reduced CD8 T-cell responses following the emergence of the Omicron variant.</p><p><strong>Results: </strong>Our findings revealed that mutant epitopes in the Omicron variant led to escape from antigen presentation and diminished CD8 T-cell immune responses. We identified two epitopes associated with decreased CD8 T-cell reactivity post-Omicron variant emergence. Notably, we discovered an S protein epitope, 67A>V, which demonstrated similar proportions of CD8 T-cell specificity between the ancestral and mutant strains, suggesting its conservation and potential immunogenicity for vaccine development. Furthermore, the third dose of the inactivated vaccine significantly increased the number of epitope-specific CD8 T cells, underscoring the importance of booster doses in enhancing cellular immune responses against the Omicron variant.</p><p><strong>Discussion: </strong>This study highlights the ability of the Omicron variant to evade CD8 T-cell immune responses through epitope mutations, while also identifying conserved epitopes with potential utility in vaccine design. The observed increase in epitope-specific CD8 T cells following a booster dose emphasizes the critical role of additional vaccinations in strengthening cellular immunity against emerging SARS-CoV-2 variants. These findings provide valuable insights for the development of next-generation vaccines targeting conserved epitopes and optimizing booster strategies.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1534530"},"PeriodicalIF":5.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11958996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular characteristics and cancer immunity of LRP1B and its relationship with the Hedgehog signaling pathway in colorectal cancer.","authors":"Yuan Liu, Yang Zhong, Yaodong Sang, Siqiang Zhu, Kang Xu, Xingyu Zhu, Xiaoling Cui, Xinyu Liu, Xiaohan Wang, Hao Chen, Changqing Jing, Wei Chong, Leping Li","doi":"10.3389/fimmu.2025.1567102","DOIUrl":"10.3389/fimmu.2025.1567102","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is a malignant tumor of the digestive tract that significantly impacts human health. LDL receptor-related protein 1B (LRP1B) may play a crucial role in tumorigenesis and disease progression.</p><p><strong>Methods: </strong>We performed a comparative analysis of differential gene expression, mutation patterns, drug sensitivity, and cellular phenotypes across different subgroups with varying LRP1B expression levels. Cellular and molecular experiments were conducted to validate our findings.</p><p><strong>Results: </strong>Our analysis implicated LRP1B as a tumor suppressor gene. Experimental results confirmed that LRP1B expression was reduced in CRC and its knockdown was associated with poor prognosis. Molecular mechanism studies revealed that LRP1B negatively regulated the Hedgehog (Hh) signaling pathway, influencing cell cycle and apoptosis processes. Single-cell analysis showed significant differences in the infiltration of T cells, B cells, epithelial cells, and myeloid cells between high and low LRP1B expression groups. Immune cell infiltration and drug sensitivity analyses demonstrated that LRP1B plays a crucial role in immunotherapy and targeted therapy, suggesting that restoring LRP1B function could be a promising treatment strategy for CRC.</p><p><strong>Conclusion: </strong>Our results indicate that LRP1B may function as a tumor suppressor factor in CRC, playing a significant role in mutation, therapy, and immune infiltration. Knockdown of LRP1B activates the Hh pathway in tumor cells, leading to the inhibition of several malignant biological behaviors.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1567102"},"PeriodicalIF":5.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T and B cell responses in different immunization scenarios for COVID-19: a narrative review.","authors":"Eva Piano Mortari, Francesca Ferrucci, Irini Zografaki, Rita Carsetti, Luciano Pacelli","doi":"10.3389/fimmu.2025.1535014","DOIUrl":"10.3389/fimmu.2025.1535014","url":null,"abstract":"<p><p>Vaccines against COVID-19 have high efficacy and low rates of adverse events. However, none of the available vaccines provide sterilizing immunity, and reinfections remain possible. This review aims to summarize the immunological responses elicited by different immunization strategies, examining the roles of homologous and heterologous vaccination and hybrid immunity. Homologous vaccination regimens exhibit considerable variation in immune responses depending on the vaccine platform, particularly concerning antibody titers, B cell activation, and T cell responses. mRNA vaccines, such as mRNA-1273 and BNT162b2, consistently generate higher and more durable levels of neutralizing antibodies and memory B cells compared to adenovirus-based vaccines like Ad26.COV2.S and ChAdOx1. The combination of two distinct vaccine platforms, each targeting different immune pathways, seems to be more effective in promoting long-lasting B cell responses and potent T cell responses. The high heterogeneity of the available studies, the different dosing schemes, the succession of new variants, and the subjects' immunological background do not allow for a definitive conclusion. Overall, heterologous vaccination strategies, combining sequentially viral vector and mRNA may deliver a more balanced and robust humoral and cellular immune response compared to homologous regimens. Hybrid immunity, which arises from SARS-CoV-2 infection preceded or followed by vaccination produces markedly stronger immune responses than either vaccination or infection alone. The immune response to SARS-CoV-2 variants of concern varies depending on both the vaccine platform and prior infection status. Hybrid immunity leads to a broader antibody repertoire, providing enhanced neutralization of variants of concern. Heterologous vaccination and hybrid immunity may provide further opportunities to enhance immune responses, offering broader protection and greater durability of immunity. However, from all-cause mortality, symptomatic or severe COVID, and serious adverse events at present it is not possible to infer different effects between homologous and heterologous schemes. Next-generation vaccines could involve tweaks to these designs or changes to delivery mechanisms that might improve performance.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1535014"},"PeriodicalIF":5.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Degradation of IL-4Ralpha by Immunoproteasome: implication in airway type 2 inflammation and hyperresponsiveness.","authors":"Niccolette Schaunaman, Diana Cervantes, Deborah A Ferrington, Hong Wei Chu","doi":"10.3389/fimmu.2025.1501898","DOIUrl":"10.3389/fimmu.2025.1501898","url":null,"abstract":"<p><strong>Introduction: </strong>Immunoproteasome (IP) is induced by pro-inflammatory stimuli such as interferon gamma to regulate inflammation and immunity. Asthma patients with airway type 2 high inflammation (e.g., IL-13) demonstrate more eosinophils and airway hyperresponsiveness (AHR) with less interferon gamma. The role of IP in regulating airway eosinophilic inflammation and AHR has not been investigated.</p><p><strong>Methods: </strong>This study was aimed to determine how IP regulates type 2 inflammation and AHR using LMP7 (a subunit of IP) deficient mouse lungs, precision-cut lung slices (PCLS), and cultured human airway epithelial cells treated with IL-13 in the absence or presence of an IP inhibitor ONX-0914 or exogenous IP.</p><p><strong>Results: </strong>LMP7 KO mouse lungs had significantly more IL-4Rα protein expression than the wildtype (WT) mice. Following IL-13 treatment in PCLS, LMP7 KO mice had significantly more airway contraction than WT mice, which was coupled with increased eotaxin-2 levels. IP inhibition by ONX-0914 in IL-13 treated human airway epithelial cells resulted in significantly more IL-4Rα protein expression and eotaxin-3 release. IP inhibition in human PCLS significantly increased AHR.</p><p><strong>Conclusion: </strong>Collectively, these data demonstrated that IP promotes degradation of IL-4Rα, while inhibits type 2 inflammation and AHR. Enhancement of IP expression or activity may serve as an alternative approach to reduce the severity of type 2 inflammation and AHR.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1501898"},"PeriodicalIF":5.7,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11958175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}