ImmunoHorizons最新文献

{"title":"Lipid A mimetic BECC438 potentiates durable and balanced antibody responses in an ovalbumin murine model of vaccination.","authors":"Erin M Harberts, James K Fields, Junela Cecille S Hunat, Danylle M Otteni, Francesca M Gardner, David J Varisco, Eric J Sundberg, Greg A Snyder, Robert K Ernst","doi":"10.1093/immhor/vlaf038","DOIUrl":"10.1093/immhor/vlaf038","url":null,"abstract":"<p><p>The need for effective infectious disease vaccines has become an inescapable topic in recent years. Continued development of next-generation vaccines that provide robust protective immunity is imperative. Such vaccines will likely include adjuvants that avoid excessive adverse reactions while allowing for dose and antigen sparing. Bacterially derived TLR4 agonist, BECC438, has recently emerged as a lead adjuvant candidate across several experimental models of infectious disease, including Yersinia pestis (plague), human papillomavirus, influenza A (flu), SARS-CoV-2 (COVID-19), and Shigella spp (gastrointestinal infection). To confirm that BECC438 is a high-quality immunoadjuvant, even without antigen from an infectious pathogen, studies presented here use the model antigen ovalbumin in a murine prime-boost vaccine model. Durable and more balanced production of antibody isotypes IgG1 and IgG2 is observed when the bacterial enzyme combinatorial chemistry adjuvant is used, as compared with the classic adjuvants aluminum salts (Alhydrogel) and synthetic monophosphorylated lipid A-PHAD (phosphorylated hexaacyl disaccharide). Antibody responses are maintained for at least 18 wk postvaccination. Observed immune metrics maintained similar trends across males, females, and genetic backgrounds, including C57BL/6, BALB/c, and CD-1 (outbred) mice, with males overall showing a lower production of IgG2c. In vitro analysis of C57BL/6 serum showed an increased half-life of ovalbumin-specific antibodies in BECC438 adjuvanted animals, indicative of a higher antigen binding affinity. These studies provide continued evidence to support the development of the BECC438 adjuvant in vaccines for human use.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Detection of pre-existing immunity to bacterial Cas9 proteins in people with cystic fibrosis.","authors":"Gregory Serpa, Qiaoke Gong, Mithu De, Pranav S J B Rana, Christopher P Montgomery, Daniel J Wozniak, Matthew E Long, Emily A Hemann","doi":"10.1093/immhor/vlaf041","DOIUrl":"10.1093/immhor/vlaf041","url":null,"abstract":"<p><p>Cystic fibrosis (CF) is caused by homozygous mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in multi-organ dysfunction and decreased lifespan and quality of life. A durable cure for CF will likely require a gene therapy approach to correct CFTR. Rapid advancements in genome editing technologies, including CRISPR/Cas9, have already resulted in Food and Drug Administration (FDA) approval for cell-based gene editing therapies, providing new therapeutic avenues for many rare diseases. However, immune responses to gene therapy delivery vectors and editing tools remain a challenge, especially for strategies targeting complex in vivo tissues such as the lung. Previous findings in non-CF healthy individuals reported pre-existing antibody and T cell responses to recombinant Cas9 proteins, suggesting potential additional obstacles for incorporation of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technologies in gene therapies. To determine whether pre-existing immunity to Cas9 from S. aureus or S. pyogenes was present or augmented in people with CF, anti-Cas9 IgG levels and Cas9-specific T cell responses were determined from peripheral blood samples of people with CF and non-CF healthy controls. Overall, non-CF control and CF samples displayed evidence of pre-existing antibody and T cell responses to both S. aureus and S. pyogenes Cas9, although there were no significant differences between these populations. However, we observed global changes in CF activation of Th1 and CD8 T cell responses as measured by interferon γ (IFN-γ) and tumor necrosis factor (TNF) that warrant further investigation and mechanistic understanding as this finding has implications not only for CRISPR/Cas9 gene therapy for people with CF but also for protection against infectious disease.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LIGHT in combination with IL-13 or IL-17 drives inflammatory transcriptional signatures in human pulmonary fibroblasts relevant for human lung disease.","authors":"Nandita Ghosh, Rinkesh Kumar Gupta, Jeamin Jung, Kai Fung, Michael Croft","doi":"10.1093/immhor/vlaf042","DOIUrl":"10.1093/immhor/vlaf042","url":null,"abstract":"<p><p>Fibroblasts are structural cells primarily involved in tissue remodeling, but recent single-cell RNA sequencing (RNA-seq) transcriptomic data have highlighted their potential to display molecules linked to inflammation. The factors that drive such inflammatory transcriptional signatures found in patients are not clear. LIGHT (TNFSF14) is a cytokine that we previously suggested may be central to lung diseases exhibiting fibrosis and inflammation, including asthma and interstitial lung disease. With bulk RNA-seq, we then investigated the transcriptional activity of LIGHT in human pulmonary fibroblasts compared with interleukin (IL)-13 and IL-17, two other cytokines linked to lung disease. While all 3 cytokines individually induced unique and overlapping gene transcripts, when fibroblasts were stimulated with LIGHT and IL-13 they upregulated more inflammatory transcripts including CCL2, CCL26, CXCL2, CXCL3, CXCL5, CXCL6, IL32, CSF2, VCAM1, ICAM1, IL18R1, IL1RL1, TNFRSF12A, TNFRSF4, TNFRSF8, ITGA2, ITGA4, and ITGAV, and when stimulated with LIGHT and IL-17, inflammatory transcripts included CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, IL32, IL33, CSF2, TSLP, IL1A, IL6, IL18, VCAM1, ICAM1, IL18R1, IL1RL1, TNFSF4, TNFRSF4, TNFRSF8, ITGA2, ITGA4, and ITGAV. Furthermore, multiple cell cycle-related transcripts were induced with these combinations. Providing potential disease significance, portions of the fibroblast transcriptional signatures induced in vitro were found to be present in subsets of fibroblasts defined by single-cell RNA-seq isolated from patients with interstitial lung disease. This study therefore highlights the synergistic activities of LIGHT with other classical cytokines to regulate transcription in pulmonary fibroblasts and infers the involvement of LIGHT in shaping fibroblast phenotypes observed in chronic lung disease.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic discoveries in hypermobile Ehlers-Danlos syndrome reveal insights into disease pathophysiology.","authors":"Molly Griggs, Victoria Daylor, Taylor Petrucci, Amy Weintraub, Matthew Huff, Sofia Willey, Kathryn Byerly, Brian Loizzi, Jordan Morningstar, Lauren Elizabeth Ball, Jennifer R Bethard, Richard Drake, Amol Sharma, Josef K Eichinger, Michelle Nichols, Steven Kautz, Steven Shapiro, Anne Maitland, Sunil Patel, Russell A Norris, Cortney Gensemer","doi":"10.1093/immhor/vlaf044","DOIUrl":"10.1093/immhor/vlaf044","url":null,"abstract":"<p><p>Hypermobile Ehlers-Danlos Syndrome (hEDS) is a poorly understood connective tissue disorder that lacks molecular diagnostic markers. This study aimed to identify proteomic signatures associated with hEDS to define underlying pathophysiology and to inform objective diagnostic strategies with therapeutic potential. An unbiased mass spectrometry-based proteomic analysis of serum from female hEDS patients (n = 29) and matched controls (n = 29) was conducted. Differentially abundant proteins were analyzed through pathway enrichment and gene ontology pipelines. Prioritized candidate biomarker proteins were verified in expanded patient and control cohorts via ELISA. Cytokine array profiling was conducted to assess immune signaling patterns. Proteomic analysis revealed 35 differentially expressed proteins in hEDS, with 43% involved in the complement cascade and 80% linked to immune, coagulation, or inflammatory pathways. Pathway analyses confirmed enrichment in complement activation, coagulation, and stress responses. ELISA validation showed significant reductions in C1QA, C3, C8A, C8B, and C9 in hEDS patients, consistent across age and sex. Cytokine profiling revealed alterations in nodal immune cell mediators in hEDS patients, supporting a model of dysregulated inflammatory response. Our findings indicate a systemic immune dysregulation, particularly involving the complement system and profibrotic cytokines, as a common feature in hEDS pathophysiology. These findings challenge the traditional view of hEDS as solely a connective tissue disorder and support a revised paradigm that includes innate immune dysfunction. This immune involvement may contribute to disease pathophysiology and inform the development of biologically based diagnostic tools, enabling earlier diagnosis and guiding future therapeutic strategies.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor cells upregulate CCL22 in a STING-dependent manner in response to paracrine factors released by STING-activated myeloid cells and type I interferons.","authors":"Elmira M Lomashvili, Jihyun Kim, Lingwei Kong, Pamela R Cook","doi":"10.1093/immhor/vlaf048","DOIUrl":"https://doi.org/10.1093/immhor/vlaf048","url":null,"abstract":"<p><p>Immunosuppressive elements within the tumor microenvironment include both regulatory T cells (Tregs) and M2 macrophages. A well-described mechanism of Treg recruitment occurs via the chemokine CCL22, and CCL22 has also recently been implicated in the polarization of tumor-associated macrophages to the M2a subtype. Our lab and others have shown that CCL22 is upregulated in cancer cells following activation of the stimulator of interferon genes (STING). STING triggers immune responses against pathogenic nucleic acids as well as self-DNA mislocalized to the cytoplasm, which can accumulate in cancer cells due to chromosomal instability, damaged mitochondria, and increased expression of LINE-1 retrotransposons. STING activation has been associated with both anti-tumor and pro-tumor immune responses, and a potential mechanism of STING-mediated immune evasion is through CCL22 upregulation. CCL22 was first characterized in macrophages, and here we investigate the effects of STING activation on CCL22 expression in macrophages and monocytes. We report that human macrophages and monocytes are resistant to CCL22 upregulation by STING, but that STING-activated macrophages and monocytes release unidentified paracrine factor(s) that dramatically increase CCL22 upregulation in cancer cells in a manner that remains STING-dependent, as evidenced by the inability of STING knockout cells to upregulate CCL22 in response to these factors. We further found that exogenous type I interferons, a major downstream product of STING activation, also upregulate CCL22 in cancer cells via a STING-dependent mechanism and that exogenous IFN-β can directly activate STING.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic deletion of Alx/Fpr2 differentially regulates pulmonary inflammation in the absence and presence of acute lung injury.","authors":"Rafia Virk, Madeline Behee, Abrar Al-Shaer, Megan Wagner, Michael Armstrong, Nichole Reisdorph, Brooke Bathon, Nari Beatty, Traci Davis, Michael J Yaeger, Rosemary S Gray, Meagan D Bridges, Kymberly M Gowdy, Saame Raza Shaikh","doi":"10.1093/immhor/vlaf043","DOIUrl":"10.1093/immhor/vlaf043","url":null,"abstract":"<p><p>The inflammation resolution receptor lipoxin A4/formyl peptide receptor 2 (ALX/FPR2) plays a critical role in immune regulation by binding select oxylipins derived from n-6 and n-3 polyunsaturated fatty acids (PUFAs). While ALX/FPR2 is implicated in controlling inflammation initiation and resolution, its specific role in pulmonary inflammatory responses remains unclear. In this study, we investigated how genetic deletion of Alx/Fpr2 controls oxylipin levels, immune cell populations, and inflammatory cytokines under conditions of homeostasis and injury. Alx/Fpr2 knockout (KO) mice exhibited normal food intake and weight gain but showed impaired glucose and lipid metabolism. Targeted lipidomic analyses by liquid chromatography-tandem mass spectrometry revealed elevated pulmonary concentrations of n-6 and n-3 PUFA-derived oxylipins in KO mice compared to controls. Flow cytometry further demonstrated increased lung infiltration of NK cells, monocytes, and lymphoid cells, indicating a proinflammatory state in the absence of injury. Following 24 h of LPS-induced acute lung injury, IL-1β levels were elevated in KO mice, but pulmonary histopathology, immune cell numbers, and oxylipin levels were comparable to those of controls. These results suggested a protective role of ALX/FPR2 upon acute lung injury, which led us to further investigate the role of ALX/FPR2 upon 72 h of lung injury. Indeed, Alx/Fpr2 KO mice showed reduced bronchoalveolar lavage protein concentration and lower levels of IL-6 and TNF-α. Collectively, these findings demonstrate that ALX/FPR2 deficiency promotes basal pulmonary inflammation but protects against prolonged injury-induced inflammation, highlighting the context-dependent role of this receptor in pulmonary inflammation.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in donor T cell targeting of host splenocyte subpopulations in acute and chronic murine graft-vs-host disease: results from a novel induction and assessment protocol with implications for lupus-like autoimmunity.","authors":"Kateryna Soloviova, Charles S Via","doi":"10.1093/immhor/vlaf039","DOIUrl":"10.1093/immhor/vlaf039","url":null,"abstract":"<p><p>Using the parent-into-F1 mouse model, we compared in vivo sex differences in acute graft-vs-host (GVHD) disease, a Th1- response and in chronic GVHD, a T follicular helper cell (Tfh) lupus-like antibody response. Using a novel induction protocol standardized for donor CD8 content, we analyzed both a sub-threshold and a supra-threshold dose for twenty flow cytometry outcome variables encompassing splenic subsets and T cell activation markers. A large majority (≥16) of the outcome variables identified significant differences in the two phenotypes, many with very large effect sizes. In acute GVHD, B cells exhibited the greatest degree of depletion in both sexes; however, the male response was significantly stronger. Sex differences in chronic GVHD were more widespread; females exhibited significantly greater numbers of total splenocytes and host CD4 T cells, Tfh cells, B cells and CD8 T cells consistent with greater female autoantibody production in this model. The more potent male CTL response in acute GVHD conflicts with reports of greater female CTL responses following infections or vaccines possibly reflecting the absence of exogenous innate immune stimuli in the GVHD model. To our knowledge, this study is the first to compare sex differences in splenic cellular composition and T cell activation for acute and chronic GVHD mice at 2 wk post-induction using 2 different doses of donor splenocytes standardized to CD8 T cell numbers and using an expanded number of outcome variables. The implications for lupus pathogenesis are discussed.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The cat's out of the bag: Toxoplasma gondii provides further insight into myeloid-mediated host defense.","authors":"Madison L Schanz, Fengdi Zhao, Kamryn E Zadeii, Li Chen, Américo H López-Yglesias","doi":"10.1093/immhor/vlaf037","DOIUrl":"https://doi.org/10.1093/immhor/vlaf037","url":null,"abstract":"<p><p>The obligate intracellular protozoan pathogen Toxoplasma gondii is estimated to infect a third of the world's population. Toxoplasmosis is considered a significant worldwide disease that can lead to morbidity or death in immunocompromised individuals. Host defense against T. gondii has been demonstrated to be dependent on a rapid myeloid cell and lymphocyte response working in concert to quickly eliminate the invading pathogen. Classically, T-bet-dependent group 1 innate lymphocytes (ILC1s), natural killer (NK) cells, and CD4+ T cell-derived interferon-γ (IFN-γ) are considered indispensable for host resistance against T. gondii. However, recent discoveries have illustrated that T-bet is not required for NK cell- or CD4+ T cell-derived IFN-γ. Yet, lack of T-bet still results in rapid mortality, pointing to a T-bet-dependent myeloid cell-mediated host defense pathway. This review summarizes the myeloid cell-mediated immune response against T. gondii and provides insights into the lesser known components of the T-bet-dependent myeloid cell-dependent host defense pathway for pathogen clearance.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12377914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The canine T cell receptor repertoire.","authors":"David Allaway, Matt Harrison, Claire Pink, Richard Haydock, Anitha Devi Jayaprakash, Ravi Sachidanandam","doi":"10.1093/immhor/vlaf040","DOIUrl":"https://doi.org/10.1093/immhor/vlaf040","url":null,"abstract":"<p><strong>Background: </strong>Tseek is a method of sequencing T cell receptor (TCR) repertoires with minimal bias. This work aimed to develop methods to characterize the TCR repertoire in dogs, identify influences such as genetic lineage and age, and evaluate the use of repertoires to monitor immune status in dogs.</p><p><strong>Methods: </strong>Two studies were conducted to develop the techniques and characterize the effect of individual, breed, and age. One study analyzed RNA data from individuals (n = 32), 8 from each of 4 breeds, sampled at 2 time points a year apart. The second, lifestage study, used individuals within a single breed (Labrador Retriever) with ages dispersed across a broad range (0.2 to 12 yr, n = 50). Tseek was used to process samples for sequencing, to identify the V, and J segments to annotate the CDR3, which were then analyzed to draw inferences.</p><p><strong>Results: </strong>The TCR repertoires had signatures of breeds, and of the individual, with stability over at least a year. Across the lifestage study, littermate-specific characteristics were not detected, but an age-related effect was observed: older dogs exhibited reduced diversity characterized by a greater abundance of individual-specific high-frequency clones, while puppies had a more diverse repertoire.</p><p><strong>Conclusion: </strong>An individual's TCR repertoire includes stable information, indicative of the individual, breed, and age-related decline. The α and β chain repertoires had distinct properties in the breed-specific signatures, indicating differential influences on their selection, despite their pairing in each T cell. Consistent, age-related changes can be seen in the repertoire, but their impact on immune system needs to be delineated.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12377913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-4 and TGF-β regulate inflammatory cytokines and cellular infiltration in the lung and systemic IL-6 in mouse-adapted SARS-CoV-2 infection.","authors":"Solomon Taye Sima, Lucinda Puebla-Clark, Maria Gonzalez-Orozco, Mark Joseph Endrino, Thomas R Shelite, Hsiang-Chi Tseng, Yazmin B Martinez-Martinez, Matthew B Huante, Hannah G Federman, Komi Gbedande, Vineet D Menachery, Mark C Siracusa, Mark A Endsley, Sara M Dann, Janice J Endsley, Ricardo Rajsbaum, Robin Stephens","doi":"10.1093/immhor/vlaf032","DOIUrl":"10.1093/immhor/vlaf032","url":null,"abstract":"<p><p>The pathology of severe COVID-19 is due to a hyperinflammatory immune response persisting after viral clearance. To understand how the immune response to SARS-CoV-2 is regulated to avoid severe COVID-19, we tested relevant immunoregulatory cytokines. Transforming growth factor β (TGF-β), interleukin (IL)-10, and IL-4 were neutralized upon infection with mouse-adapted SARS-CoV-2 (CMA3p20), a model of mild disease; lung inflammation was quantified by histology and flow cytometry at early and late time points. Mild weight loss and lung inflammation including consolidation and alveolar thickening were evident 3 d postinfection (dpi), and inflammation persisted to 7 dpi. Coinciding with early monocytic infiltrates, CCL2 and granulocyte colony-stimulating factor were transiently produced 3 dpi, while IL-12 and CCL5 persisted to 7 dpi, modeling viral and inflammatory phases of disease. Neutralization of TGF-β, but not IL-10 or IL-4, significantly increased lung inflammatory monocytes and elevated serum but not lung IL-6. Neutralization of IL-4 prolonged weight loss and increased early perivascular infiltration without changing viral titer. Anti-IL-4 reduced expression of Arg1, a gene associated with alternative activation of macrophages. Neutralizing TGF-β and IL-4 had differential effects on pathology after virus control. Lung perivascular infiltration was reduced 7 dpi by neutralization of IL-4 or TGF-β, and periairway inflammation was affected by anti-TGF-β, while alveolar infiltrates were not affected by either. Anti-IL-4 prolonged IL-12 to 7 dpi along with reduced IL-10 in lungs. Overall, the immunoregulatory cytokines TGF-β and IL-4 dampen initial inflammation in this mouse-adapted SARS-CoV-2 infection, suggesting that promotion of immunoregulation could help patients in early stages of disease.</p>","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":"9 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12377903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144983492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}