https://scholars.lib.ntu.edu.tw/handle/123456789/623929
標題: | HLJ1 amplifies endotoxin-induced sepsis severity by promoting IL-12 heterodimerization in macrophages | 作者: | Luo, Wei-Jia SUNG-LIANG YU Chang, Chia-Ching Chien, Min-Hui Chang, Ya-Ling Liao, Keng-Mao Lin, Pei-Chun KUEI-PIN CHUNG YA-HUI CHUANG Chen, Jeremy J W PAN-CHYR YANG KANG-YI SU |
關鍵字: | DNAJB4; HLJ1; IFN-γ; IL-12; cell biology; immunology; inflammation; lipopolysaccharide; mouse; sepsis | 公開日期: | 2022 | 卷: | 11 | 來源出版物: | eLife | 摘要: | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/623929 | ISSN: | 2050-084X | DOI: | 10.7554/eLife.76094 |
顯示於: | 醫學院附設醫院 (臺大醫院) |
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