The following is a summary of “Extracellular histones exacerbate heat stroke-induced liver injury by triggering hepatocyte pyroptosis and liver injury via the TLR9-NLRP3 pathway,” published in the January 2024 issue of Oncology by Li et al.

Severe heat stroke often triggers multi-organ failure, including liver injury, attributed to sterile inflammation initiated by cellular damage. Within this context, activating the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in hepatocytes and subsequent pyroptosis are recognized as pivotal mechanisms. Given that extracellular histones act as damage-associated molecular patterns, inducing tissue toxicity and inflammation, their study aimed to explore their potential contribution to hepatocyte pyroptosis after heat stroke, thereby exacerbating liver inflammation and injury.

Using AML-12 murine hepatocytes aged 8–12 weeks subjected to hyperthermia, they administered exogenous histones following heat exposure. Before heat treatment, they neutralized endogenous histones using specific antibodies, inhibited inflammasome assembly through RNA silencing, and modulated Toll-like receptor 9 (TLR9) activity using pharmacological agonists or antagonists. Assessments included evaluating inflammasome assembly, caspase-1 activation, histological alterations, and levels of liver enzymes. Statistical analyses employed one-way ANOVA with Tukey’s post-hoc testing for comparisons among multiple groups and Pearson’s correlation test for correlation analyses. The experiments were conducted in triplicate, and significance was set at p < 0.05.

Their results demonstrated that heat stroke led to the release of histones into the extracellular space, correlating with liver injury severity. Notably, extracellular histones exacerbated heat stroke-induced liver injury both in vitro and in vivo in a manner dependent on dose and duration. Conversely, neutralizing histones conferred protection against heat stroke-induced injury. Mechanistically, histones facilitated the activation of the NLRP3 inflammasome via the Toll-like receptor 9 (TLR9) signaling pathway, leading to hepatocyte pyroptosis and subsequent liver inflammation.

Their findings underscore the critical role of histones as mediators of hepatocyte pyroptosis, exacerbating liver injury in the context of heat stroke. Consequently, targeting extracellular histones might hold therapeutic promise in mitigating heat stroke-induced cell death and liver damage. This suggests a potential avenue for therapeutic intervention to ameliorate heat stroke-induced liver injury.

Source: sciencedirect.com/science/article/abs/pii/S1567576923016326