CRISPLD2 attenuates pro-inflammatory cytokines production in HMGB1-stimulated monocytes and septic mice.

HMGB1 has been identified as a pro-inflammatory mediator which leads to sepsis lethality. Previous studies suggested that CRISPLD2 had anti-inflammatory property and might severe as a therapeutic agent in sepsis. In the present study, we first conducted bioinformatic analysis to explore the expression profile of HMGB1 in septic survivors and non-survivors. We found that the serum HMGB1 level of septic non-survivors was significantly higher than that of septic survivors, and there was a positive correlation between CRISPLD2 and HMGB1 in mRNA expression in most of the cancer and normal tissue types, revealing a co-expression or dependency relationship between the two genes. In vitro, using cultured THP-1 cells, we confirmed that HMGB1 can induce the expression of CRISPLD2 in a time dependent manner through TLR4-dependent pathway. Given that CRISPLD2 and HMGB1 shared a wide range of time scales in gene expression and the anti-inflammatory property of CRISPLD2, we further verified that HMGB1 induced cytokines production might be partially reversed by CRISPLD2. In vivo, intravenously treatment of CRISPLD2 failed to rescue septic mice, although the serum levels of inflammatory cytokines were decreased. In conclusion, our study demonstrated that HMGB1 can act as stimuli to up-regulate the expression of CRISPLD2 in THP-1 cells, and in turn, increased CRISPLD2 can curtail HMGB1 induced pro-inflammatory cytokines production. Unfortunately, the anti-inflammatory effects of CRISPLD2 did not translate into survival benefit in mice with sepsis. AJTR