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

Introduction: 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. Methods: 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. Results: 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. Discussion: 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.