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During lipopolysaccharide (LPS)-induced endotoxic shock, HLJ1 knockout mice shows reduced organ injury and IFN-\u03b3 (interferon-\u03b3)-dependent mortality. Using single-cell RNA sequencing, we characterize mouse liver nonparenchymal cell populations under LPS stimulation, and show that HLJ1 deletion affected IFN-\u03b3-related gene signatures in distinct immune cell clusters. In CLP models, HLJ1 deletion reduces IFN-\u03b3 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-\u03b3 in natural killer cells but not CD4\n                    <jats:sup>+<\/jats:sup>\n                    or CD8\n                    <jats:sup>+<\/jats:sup>\n                    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-\u03b3 levels and protects the mice from IFN-\u03b3-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-\u03b3-dependent septic lethality by promoting IL-12 heterodimerization, and targeting HLJ1 has therapeutic potential in inflammatory diseases involving activated IL-12\/IFN-\u03b3 axis.\n                  <\/jats:p>","DOI":"10.7554\/elife.76094","type":"journal-article","created":{"date-parts":[[2022,8,19]],"date-time":"2022-08-19T08:00:21Z","timestamp":1660896021000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.76094","source":"Crossref","is-referenced-by-count":20,"title":["HLJ1 amplifies endotoxin-induced sepsis severity by promoting IL-12 heterodimerization in macrophages"],"prefix":"10.7554","volume":"11","author":[{"given":"Wei-Jia","family":"Luo","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05bqach95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University","place":["Taipei, 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