Role of Intracellular Toll Like Receptors (TLRs) in the Secondary Events of Traumatic Brain Injury

Abstract

The mechanisms underlying secondary brain damage following traumatic brain injury (TBI) is still unclear. Many studies demonstrated that inflammatory cascades contribute to brain damage through the activation of immune/inflammatory responses, including the increased release of cytokines and chemokines as well as the recruitment of leukocytes. The cells and tissues damaged by primary mechanical injury released a number of endogenous factors acting as damage‐associated molecular patterns (DAMPs), which initiate and perpetuate noninfectious inflammatory responses through transduction signaling pathways. Toll‐like receptors (TLRs) are a transmembrane receptor family that can recognize the specific DAMPs released from damaged cells and recruit a set of adaptors leading to the activation of downstream kinases and nuclear factors which regulate the expression of inflammatory genes. The activation of inflammatory responses mediated by TLR signaling is closely associated with brain tissue damage and neurological dysfunction following TBI. Since the role of intracellular TLRs such as 7, 8 and 9 after TBI is still unclear, we decided to evaluate the outcome and the secondary brain damage after TBI in TLR 7/8−/−and TLR 7/9−/−double KO mice. We performed a TBI, using a validate experimental model of controlled cortical impact injury (CCI), both TLR 7/8−/−and TLR 7/9−/−and in wild type (WT) mice. 24h thereafter we evaluated the contusion volume, the brain edema formation, the expression of pro‐inflammatory cytokines as well as the activation of immune response.Thus the obtained results demonstrated that modulation of intracellular TLR‐mediated signaling may attenuate brain damage and improve TBI outcome. Therefore, the intracellular TLRs and their downstream protein kinases may be potential targets for the treatment of TBI.