Inhibition of tumor necrosis factor receptor-associated factor 6 alleviates secondary brain injury by reducing neuronal pyroptosis after intracerebral hemorrhage.

Secondary brain injury (SBI) is one of the main causes of high mortality and disability rates following intracerebral hemorrhage (ICH). Tumor necrosis factor receptor-associated factor 6 (TRAF6) plays a crucial role in the process of pyroptosis, and modulating its expression may present a novel therapeutic strategy for mitigating brain injury. This study aims to explore the mechanisms of TRAF6 in pyroptosis after ICH. C57BL/6J mice were used to establish the ICH model. Brain was collected at different time points for q-PCR and western blot to detect the level of TRAF6. After the C25-140 (the TRAF6 inhibitor) was administrated, the mice were divided into four groups. Then, the neurological deficit, brain water content, and blood-brain barrier (BBB) damage were detected. Immunofluorescence and western blot were used to detect the level of pyroptosis proteins, and ELISA and q-PCR were used to detect the levels of IL-18 and IL-1β. TRAF6 expression was upregulated after ICH and was mainly expressed in neurons. Inhibition of TRAF6 expression with C25-140 alleviated neurological deficits and reduced brain edema after ICH. In addition, inhibition of TRAF6 also reduced the expression of pyroptosis inflammasomes such as GSDMD, NLRP3, and ASC, as well as neurological damage caused by IL-18 and IL-1β after ICH. TRAF6 regulates neuronal pyroptosis in SBI after ICH. Inhibition of TRAF6 may be a potential target for alleviating inflammatory damage after ICH.