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 (CCl)-induced ALI in mice. Removal of the source of serum Prdx1 protected mice deficient in Prdx1 from APAP and CCl-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.