HMGB1 Derived from the Pyroptotic Microenvironment Promotes Macrophage Extracellular Traps in Hirschsprung-Associated Enterocolitis

Hirschsprung-associated enterocolitis (HAEC) is the most common and severe complication in patients with Hirschsprung's disease (HSCR) and is characterized by high morbidity, frequent recurrence and substantial mortality. The formation of macrophage extracellular traps (METs), a novel inflammatory mode of cell death, plays a significant role in the progression of various inflammatory diseases. However, the mechanisms underlying METs formation and their role in the progression of HAEC remain unclear. Here, the findings indicate that METs formation induced by the pyroptotic microenvironment enhances inflammatory responses and induces colonic epithelial cells (CECs) injury in HAEC. Mechanistically, high mobility group box 1 protein (HMGB1), derived from this pyroptotic environment, mediates METs formation through Toll-like Receptor 4 (TLR4)-p38 MAPK/p65 NF-kB signaling pathways. Furthermore, incubation of CECs with METs induces suppression of cell viability, more production of Reactive Oxygen Species (ROS) and Pyroptosis. In conclusion, HMGB1 mediates the communication between pyroptotic microenvironment and METs formation, triggering enhanced inflammatory responses and damage to CECs. Targeting HMGB1 presents a potential therapeutic strategy for HAEC.

high mobility group box 1; hirschsprung‐associated enterocolitis; macrophage; macrophage extracellular traps; pyroptosis.