HLJ1 amplifies endotoxin-induced sepsis severity by promoting IL-12 heterodimerization in macrophages
Wei-Jia Luo,
Sung-Liang Yu,
Chia-Ching Chang,
Min-Hui Chien,
Ya-Ling Chang,
Keng-Mao Liao,
Pei-Chun Lin,
Kuei-Pin Chung,
Ya-Hui Chuang,
Jeremy JW Chen,
Pan-Chyr Yang,
Kang-Yi Su
Affiliations
Wei-Jia Luo
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
Sung-Liang Yu
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Center of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University, Taipei, Taiwan
Chia-Ching Chang
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
Min-Hui Chien
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
Ya-Ling Chang
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Center of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan
Keng-Mao Liao
Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan
Pei-Chun Lin
Department of Laboratory Medicine, National Taiwan University, Taipei, Taiwan
Kuei-Pin Chung
Department of Laboratory Medicine, National Taiwan University, Taipei, Taiwan
Ya-Hui Chuang
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
Jeremy JW Chen
Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
Pan-Chyr Yang
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan; Center of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan; Department of Laboratory Medicine, National Taiwan University, Taipei, Taiwan; Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan
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.
