Circulating Peroxiredoxin-1 is a novel damage-associated molecular pattern and aggravates acute liver injury via promoting inflammation

Sterile inflammation is initiated by damage-associated molecular patterns (DAMPs) and a key contributor to acute liver injury (ALI). However, the current knowledge on those DAMPs that activate hepatic inflammation under ALI remains incomplete. We report here that circulating peroxiredoxin-1 (Prdx1) is a novel DAMP for ALI. Intraperitoneal injection of acetaminophen (APAP) elicited a progressive course of ALI in mice, which was developed from 12 to 24 h post injection along with liver inflammation evident by macrophage infiltration and upregulations of cytokines (IL-1β, IL-6 and TNF-α); these alterations were concurrently occurred with a robust and progressive production of serum Prdx1. Similar observations were also obtained in carbon tetrachloride (CCl₄)-induced ALI in mice. Removal of the source of serum Prdx1 protected mice deficient in Prdx1 from APAP and CCl₄-induced liver injury, and decreased macrophage infiltration, IL-1β, IL-6 and TNF-α production. As a result, Prdx1^-/- mice were strongly protected from APAP-induced death that was likely progressed from ALI. Additionally, intravenous re-introduction of recombinant Prdx1 (rPrdx1) in Prdx1^-/- mice reversed or reduced all the above events, demonstrating an important contribution of circulating Prdx1 to ALI. rPrdx1 potently induced in primary macrophages the expression of pro-IL-1β, IL-6, TNF-α, and IL-1β through the NF-κB signaling as well as the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling, evident by caspase-1 activation. Furthermore, a significant elevation of serum Prdx1 was demonstrated in patients (n = 15) with ALI; the elevation is associated with ALI severity. Collectively, we provide the first demonstration for serum Prdx1 contributing to ALI.