Traumatic Brain Injury (TBI) triggers a loss of brain tissue and, subsequently, a strong inflammatory response in the brain. In addition, TBI can alter the function of peripheral regions and other organs, eliciting systemic responses and global consequences. A focal injury to the brain elicits a rapid hepatic response, the production of chemokines by the liver acts as an amplifier of the focal injury response providing a route of CNS-liver communication. However, little is currently known regarding the inflammatory mediators and acute-phase proteins involved in the peripheral regions after brain injury, such as the liver. Furthermore, the extent of damage TBI inflicts on the peripheral organs remains largely unexplored. Serum Amyloid A1 (SAA1) is an acute phase protein involved in the chemotactic recruitment of inflammatory cells to the site of inflammation. After tissue damage, SAA1 is mainly produced in the liver and exported via peripheral circulation, directly affecting the pathogenesis of inflammation in other organs. The role of SAA1 after TBI is unknown, however we have recently shown that TBI induces the production and release of SAA1 from the liver into the circulatory system, and our preliminary data will show that SAA1 relocates to the brain lesion where it interacts with microglial cells. In this grant proposal we will test the hypothesis that hepatic SAA1 exacerbates the brain?s inflammatory response to TBI, leading to enhanced cell death, inflammation and behavioral deficits. We will rigorously test this hypothesis using two specific aims: 1) Determine the effect of TBI severity on SAA1 expression in periphery and in the brain; 2) Investigate whether peripherally-produced SAA1 stimulates neuroinflammation, neuronal damage and behavioral dysfunction after TBI. In conclusion, since inflammation appears to be a common link between brain injury and the periphery, one is led to hypothesize that inflammatory signals released after TBI could regulate components of hepatic response and that consequently induce detrimental changes damaged brain regions. As an acute phase protein with pleiotropic pro-inflammatory properties, SAA1 may represent an important link between brain injury and hepatic and systemic inflammation. Elucidation of the role SAA1 plays in the general inflammatory response after TBI will aid in the design of more efficient therapeutic approaches for acute inflammation, using agents that most effectively suppress SAA1 and mitigating subsequent, secondary brain injury.
Brain trauma comprises an injury surrounding the impact site and local inflammation, but also triggers systematic inflammation in peripheral organs such as the liver. An injury to the brain is accompanied by a rapid response in the liver, where acute phase proteins are produced that promote an inflammatory cascade involving serum amyloid A1 (SAA1). SAA1 induces the production of more inflammatory factors, which aggravate central inflammation by activating signals that are carried back to the brain. Thus, we hypothesize in this project that blocking SAA1 production in the liver might slow down the inflammatory response in the damaged brain, providing an advantageous environment for repair and functional recovery after traumatic brain injury.
