RESUMO
Although multiple signaling pathways contributing to the pathophysiological process have been investigated, treatments for traumatic brain injury (TBI) against present targets have not acquired significant clinical progress. Interleukin-1 receptor-associated kinase 4 (IRAK4) is an important factor involved in regulating immunity and inflammation. However, the role of IRAK4 in TBI still remains largely unknown. Therefore, using a controlled cortical impact model (CCI), we investigated the function and molecular mechanism of IRAK4 in the context of TBI. IRAK4 was found to be activated in a time-dependent manner after TBI and mainly expressed in neurons. Inhibition of IRAK4 by siRNAs could significantly alleviates neuroinflammation, neuron apoptosis, brain edema, brain-blood barrier (BBB) dysfunction and improves neurological deficit in the context of CCI. Mechanistically, IRAK4 exacerbates CCI via activation of TAK1 signaling pathway. Interestingly, PF-0665083, an IRAK4 inhibitor, inhibits phosphorylation of IRAK4 and attenuates CCI-induced secondary injury. It could be conclude that IRAK4 plays a critical role in TBI-induced secondary injury and the underlining mechanism may be related to activation of TAK1 signaling pathway. PF-0665083 may serve as a potential treatment strategy to relieve TBI.