| First Author | Luo WJ | Year | 2022 |
| Journal | Elife | Volume | 11 |
| PubMed ID | 35983991 | Mgi Jnum | J:328843 |
| Mgi Id | MGI:7335639 | Doi | 10.7554/eLife.76094 |
| Citation | Luo WJ, et al. (2022) HLJ1 amplifies endotoxin-induced sepsis severity by promoting IL-12 heterodimerization in macrophages. Elife 11:e76094 |
| abstractText | 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-gamma (interferon-gamma)-dependent mortality. Using single-cell RNA sequencing, we characterize mouse liver nonparenchymal cell populations under LPS stimulation, and show that HLJ1 deletion affected IFN-gamma-related gene signatures in distinct immune cell clusters. In CLP models, HLJ1 deletion reduces IFN-gamma 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-gamma 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-gamma levels and protects the mice from IFN-gamma-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-gamma-dependent septic lethality by promoting IL-12 heterodimerization, and targeting HLJ1 has therapeutic potential in inflammatory diseases involving activated IL-12/IFN-gamma axis. |
