دورية أكاديمية
HLJ1 amplifies endotoxin-induced sepsis severity by promoting IL-12 heterodimerization in macrophages
العنوان: | HLJ1 amplifies endotoxin-induced sepsis severity by promoting IL-12 heterodimerization in macrophages |
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المؤلفون: | Luo, Wei-Jia, Yu, Sung-Liang, Chang, Chia-Ching, Chien, Min-Hui, Chang, Ya-Ling, Liao, Keng-Mao, Lin, Pei-Chun, Chung, Kuei-Pin, Chuang, Ya-Hui, Chen, Jeremy JW, Yang, Pan-Chyr, Su, Kang-Yi |
المساهمون: | Ministry of Science and Technology, Taiwan, National Taiwan University |
المصدر: | eLife ; volume 11 ; ISSN 2050-084X |
بيانات النشر: | eLife Sciences Publications, Ltd |
سنة النشر: | 2022 |
المجموعة: | eLife (E-Journal - via CrossRef) |
الوصف: | Heat shock protein (HSP) 40 has emerged as a key factor in both innate and adaptive immunity, whereas the role of HLJ1, a molecular chaperone in HSP40 family, in modulating endotoxin-induced sepsis severity is still unclear. During lipopolysaccharide (LPS)-induced endotoxic shock, HLJ1 knockout mice shows reduced organ injury and IFN-γ (interferon-γ)-dependent mortality. Using single-cell RNA sequencing, we characterize mouse liver nonparenchymal cell populations under LPS stimulation, and show that HLJ1 deletion affected IFN-γ-related gene signatures in distinct immune cell clusters. In CLP models, HLJ1 deletion reduces IFN-γ expression and sepsis mortality rate when mice are treated with antibiotics. HLJ1 deficiency also leads to reduced serum levels of IL-12 in LPS-treated mice, contributing to dampened production of IFN-γ in natural killer cells but not CD4 + or CD8 + T cells, and subsequently to improved survival rate. Adoptive transfer of HLJ1-deleted macrophages into LPS-treated mice results in reduced IL-12 and IFN-γ levels and protects the mice from IFN-γ-dependent mortality. In the context of molecular mechanisms, HLJ1 is an LPS-inducible protein in macrophages and converts misfolded IL-12p35 homodimers to monomers, which maintains bioactive IL-12p70 heterodimerization and secretion. This study suggests HLJ1 causes IFN-γ-dependent septic lethality by promoting IL-12 heterodimerization, and targeting HLJ1 has therapeutic potential in inflammatory diseases involving activated IL-12/IFN-γ axis. |
نوع الوثيقة: | article in journal/newspaper |
اللغة: | English |
DOI: | 10.7554/elife.76094 |
الإتاحة: | https://doi.org/10.7554/elife.76094Test https://cdn.elifesciences.org/articles/76094/elife-76094-v2.pdfTest https://cdn.elifesciences.org/articles/76094/elife-76094-v2.xmlTest https://elifesciences.org/articles/76094Test |
حقوق: | http://creativecommons.org/licenses/by/4.0Test/ ; http://creativecommons.org/licenses/by/4.0Test/ ; http://creativecommons.org/licenses/by/4.0Test/ |
رقم الانضمام: | edsbas.814AF532 |
قاعدة البيانات: | BASE |
DOI: | 10.7554/elife.76094 |
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