HLJ1 amplifies endotoxin-induced sepsis severity by promoting IL-12 heterodimerization in macrophages

Abstract

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 LPS-induced endotoxic shock, HLJ1 knockout mice shows reduced organ injury and IFN-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.

Plasticity and crosstalk of mesenchymal stem cells and macrophages in immunomodulation in sepsis

“…Among these, IL-12 activates natural killer (NK) cells and promotes the differentiation of T cells into Th1 effector cells, which produce IFN-γ. IFN-γ enhances the phagocytic and bactericidal functions of macrophages by mediating STAT ( 35 ). Studies have indicated that IFN-γ can ameliorate sepsis by increasing the expression of HLA-DR in monocytes and the secretion of TNF-α ( 36 ).…”

“…Concurrently, these cells recruit other immune cells to jointly increase the production of proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-a), IL-1, IL-6, IL-8, IL-12, and migration inhibitory factor (MIF). Among these, IL-12 activates natural killer (NK) cells and promotes the differentiation of T cells into Th1 effector cells, which produce IFN-g. IFN-g enhances the phagocytic and bactericidal functions of macrophages by mediating STAT (35). Studies have indicated that IFN-g can ameliorate sepsis by increasing the expression of HLA-DR in monocytes and the secretion of TNF-a (36).…”

Tumour-associated macrophages: versatile players in the tumour microenvironment

“…Furthermore, macrophages are involved in innate and adaptive immune responses by recognizing pathogen-associated molecular patterns (PAMPs) ( Greene et al, 2022 ) and damage-associated molecular patterns (DAMPs) ( Serbulea et al, 2018 ; Neu et al, 2022 ) through PRRs. Activated macrophages produce pro-inflammatory cytokines, i.e., tumour necrosis factor-alpha (TNF-α) ( Lee et al, 2021 ; Lechner et al, 2022 ; Tanito et al, 2023 ) and interleukin-12 (IL-12) ( Luo et al, 2022 ; Pfirschke et al, 2022 ), to promote inflammation and activate other immune cells. Macrophages also process and present antigens to T cells via major histocompatibility complex (MHC) molecules aiding adaptive immune response ( Mascarau et al, 2023 ; van Elsas et al, 2023 ).…”

MAP4K4 promotes chlamydial infectivity and genital tract inflammatory injury by negatively regulating protective immunity in Chlamydia infection

“…It has been shown that some cytokines such as IFN-γ, IL-12, IL-6, and TNF-α secreted by macrophages have phagocytosis, bactericidal, antigen presentation, and promotion of Th1 immunity (30)(31)(32)(33). To further explore the effect of MAP4K4 on inducing cytokine expression in Chlamydia-infected RAW 264.7 cells, we examined 32 potential cytokines and chemokines simultaneously using a mouse cytokine array microarray.…”