{ "abstract": "Helminths induce regulatory T cells (Tregs) to establish chronic infections, promoting long-term persistence of both parasites and hosts. TGF-β1 is essential for Treg induction by initiating Foxp3 expression. Helminth infections are typically associated with high TGF-β1 levels, yet the mechanisms by which helminths drive its production are not fully understood. Here, we uncover a mechanism whereby the scavenger receptor class A1 (SR-A1) cooperates with TLR4 signaling to drive TGF-β1 production by macrophages. Mechanistically, schistosome egg antigens activate TLR4-p50 (NF-κB1) while concurrently engaging SR-A1 to upregulate c-Jun, thereby assembling c-Jun-p50 transcription complexes at the Tgfb1 promoter and enhancing TGF-β1 expression, subsequently inducing Tregs and mitigating liver immunopathology in Schistosoma japonicum-infected mice. Thus, we identify a previously unrecognized host-parasite interaction wherein SR-A1-TLR4 cooperation enables helminths to manipulate macrophage transcriptional programs for TGF-β1 expression and Treg induction, identifying a potential therapeutic target in the host for inflammatory helminthiasis. Author summary: Helminth parasites have evolved sophisticated strategies to persist in their hosts for prolonged periods, largely by actively dampening immune responses. A key strategy involves inducing regulatory T cells (Tregs), a specialized subset of immune cells that maintain tolerance and curb excessive inflammation. The cytokine TGF-β1 is essential for generating protective Tregs, yet the mechanisms by which parasitic worms stimulate their production remain poorly understood. This study unveils a previously unrecognized pattern recognition receptor crosstalk axis wherein helminth co-opts SR-A1-TLR4 synergy to orchestrate host tolerogenic programs during helminth infection. Mechanistically, schistosome egg antigens activate TLR4-p50 while engaging SR-A1 to upregulate c-Jun, forming c-Jun-p50 transcription complexes that enhance Tgfb1 gene expression. This SR-A1-TLR4 axis induces regulatory T cells and mitigates liver immunopathology in infected mice. These findings illuminate a distinct host-parasite interface for governing immune homeostasis, identifying SR-A1 as a potential host-directed therapeutic target for modulating chronic parasitic immunopathology.", "abstract_shown": true, "affiliations": [ "Key Laboratory for Pathogen Infection and Control of Jiangsu Province, Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, National Vaccine Innovation Platform of Nanjing Medical University, State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, Jiangsu, China", "Department of Immunology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China", "National Health Commission Key Laboratory of Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, China", "Key Laboratory for Pathogen Infection and Control of Jiangsu Province, Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Lianyungang Medical-Education Innovation and Research Center, Nanjing Medical University, Nanjing, Jiangsu, China" ], "article_type": "Research Article", "arxiv": null, "author_total": 17, "authors": [ { "affs": [ 0 ], "name": "Junyao Shen" }, { "affs": [ 1 ], "name": "Ziling Wang" }, { "affs": [ 2 ], "name": "Chuanhong Huang" }, { "affs": [ 3 ], "name": "Weijie Xue" }, { "name": "Yu Wu" }, { "name": "Tianyu Fan" }, { "name": "Yuanyuan Miao" }, { "name": "Chenxu Mao" }, { "name": "Jiaojiao Yu" }, { "name": "Yalin Li" }, { "name": "Lei Xu" }, { "name": "Jifeng Zhu" }, { "name": "Xiaojun Chen" }, { "name": "Yang Dai" }, { "name": "Zhigang Lei" }, { "name": "Sha Zhou" }, { "name": "Chuan Su" } ], "bibtex": "https://research.draconitic.com/paper/4hs9a3tpvbqjj.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014732", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014732", "id": "4hs9a3tpvbqjj", "issns": [ "1553-7374" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014732", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/Non-coding RNA/Small interfering RNA" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/DNA-binding proteins/Transcription factors" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Regulatory proteins/Transcription factors" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/T cells/Regulatory T cells" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/T cells/Regulatory T cells" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Gene regulation/Small interfering RNA" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression/Gene regulation/Transcription factors" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/T cells/Regulatory T cells" ], [ "plos", "/Biology and life sciences/Organisms/Eukaryota/Animals/Invertebrates/Helminths" ], [ "plos", "/Biology and life sciences/Organisms/Eukaryota/Animals/Invertebrates/Helminths/Schistosoma/Schistosoma japonicum" ], [ "plos", "/Biology and life sciences/Physiology/Immune physiology/Spleen" ], [ "plos", "/Biology and life sciences/Zoology/Animals/Invertebrates/Helminths" ], [ "plos", "/Biology and life sciences/Zoology/Animals/Invertebrates/Helminths/Schistosoma/Schistosoma japonicum" ], [ "plos", "/Medicine and health sciences/Gastroenterology and hepatology/Liver diseases/Liver fibrosis" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/T cells/Regulatory T cells" ] ], "openalex": null, "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014732&type=printable", "pmcid": null, "pmid": null, "published": "2026-10-30", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/4hs9a3tpvbqjj.ris", "sources": [ { "first_seen": "2026-10-31T12:20:55Z", "native_id": "10.1371/journal.ppat.1014732", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014732" } ], "subjects": [ { "field": "biochemistry", "origin": "plos:gene expression", "subfield": "molecular-biology" }, { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" } ], "title": "SR-A1 cooperates with TLR4-NF-κB signaling to drive macrophage TGF-β1 expression and Treg induction during schistosome infection", "title_text": "SR-A1 cooperates with TLR4-NF-κB signaling to drive macrophage TGF-β1 expression and Treg induction during schistosome infection", "type": "peer-reviewed", "updated_at": "2026-11-01T12:20:45Z", "url": "https://research.draconitic.com/paper/4hs9a3tpvbqjj", "venue": "PLOS Pathogens", "versions": [] }