SR-A1 cooperates with TLR4-NF-κB signaling to drive macrophage TGF-β1 expression and Treg induction during schistosome infection
4 affiliations
- 1Key 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
- 2Department of Immunology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- 3National 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
- 4Key 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
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.
Related
- Replication-coupled chromatin assembly cooperates with ATR/CHK1 signaling to suppress DNA damage and premature MMB-dependent mitotic transcription
- ESX-5 paralog deletions in Mycobacterium tuberculosis alter macrophage cytokine signaling and bacterial heavy metal response
- PERK/ATF3-dependent induction of GDE4 modulates intracellular lysophospholipid-PPARα/γ signaling
- VEGFR2-dependent VEGFR3 expression leads to CXCL1/2 and CXCR2 induction in the development of retinal neovascularization
- Pectic Polysaccharides and Glucans in Macrophage Redox-Immune Crosstalk: Structural Determinants, Receptor Signaling, and Evidence Boundaries
BibTeX
@article{shen2026sra1,
title = {{SR-A1 cooperates with TLR4-NF-κB signaling to drive macrophage TGF-β1 expression and Treg induction during schistosome infection}},
author = {Junyao Shen and Ziling Wang and Chuanhong Huang and Weijie Xue and Yu Wu and Tianyu Fan and Yuanyuan Miao and Chenxu Mao and Jiaojiao Yu and Yalin Li and Lei Xu and Jifeng Zhu and Xiaojun Chen and Yang Dai and Zhigang Lei and Sha Zhou and Chuan Su},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014732},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014732},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SR-A1 cooperates with TLR4-NF-κB signaling to drive macrophage TGF-β1 expression and Treg induction during schistosome infection
AU - Junyao Shen
AU - Ziling Wang
AU - Chuanhong Huang
AU - Weijie Xue
AU - Yu Wu
AU - Tianyu Fan
AU - Yuanyuan Miao
AU - Chenxu Mao
AU - Jiaojiao Yu
AU - Yalin Li
AU - Lei Xu
AU - Jifeng Zhu
AU - Xiaojun Chen
AU - Yang Dai
AU - Zhigang Lei
AU - Sha Zhou
AU - Chuan Su
PY - 2026
DA - 2026/10/30
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014732
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014732
AB - 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.
SN - 1553-7374
ER -