Intertwined roles for GDF-15, HMGB1, and MIG/CXCL9 in Pediatric Acute Liver Failure

Pediatric Acute Liver Failure (PALF) presents as a rapidly evolving, multifaceted, and devastating clinical syndrome whose precise etiology remains incompletely understood. Consequently, predicting outcomes-whether survival or mortality-and informing liver transplantation decisions in PALF remain challenging. We have previously implicated High-Mobility Group Box 1 (HMGB1) as a central mediator in PALF-associated dynamic inflammation networks that could be recapitulated in acetaminophen (APAP)-treated mouse hepatocytes (HC) in vitro. Here, we hypothesized that Growth/Differentiation Factor-15 (GDF-15) is involved along with HMGB1 in PALF.

28 and 23 inflammatory mediators including HMGB1 and GDF15 were measured in serum samples from PALF patients and cell supernatants from wild-type (C57BL/6) mouse hepatocytes (HC) and from cells from HC-specific HMGB1-null mice (HC-HMGB1^-/-) exposed to APAP, respectively. Results were analyzed computationally to define statistically significant and potential causal relationships.

Circulating GDF-15 was elevated significantly (P < 0.05) in PALF non-survivors as compared to survivors, and together with HMGB1 was identified as a central node in dynamic inflammatory networks in both PALF patients and mouse HC. This analysis also pointed to MIG/CXCL9 as a differential node linking HMGB1 and GDF-15 in survivors but not in non-survivors, and, when combined with in vitro studies, suggested that MIG suppresses GDF-15-induced inflammation.

This study suggests GDF-15 as a novel PALF outcome biomarker, posits GDF-15 alongside HMGB1 as a central node within the intricate web of systemic inflammation dynamics in PALF, and infers a novel, negative regulatory role for MIG.