Microglial/macrophage Pannexin-1 channels promote neuroinflammation and blood brain barrier leakage after traumatic brain injury

Identification: Seo, Joon Ho


Microglial/macrophage Pannexin-1 channels promote neuroinflammation and blood brain barrier leakage after traumatic brain injury
Joon Ho Seo, Miloni Dalal, Frances Calderon and Jorge E. Contreras.
Department of Neuroscience, Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, USA

Neuroinflammation is a major component of secondary damage after traumatic brain injury (TBI). The activation of inflammatory cells at the injury site causes the release of pro-inflammatory cytokines and chemokines, which mediates the recruitment of more microglia and leukocytes to the injury site. If this process persists or exacerbates, it prevents the resolution of the inflammation and enhances secondary injury damage. Elevated extracellular levels of adenosine 5′-triphosphate (ATP) released upon injury have been shown to be pro-inflammatory. Recently, Pannexin-1 (Panx1) channel proteins have been identified as an important conduit for ATP release from dying cells, enhancing the inflammatory response in peripheral immune cells. Our previous work has shown that pharmacological inhibition of Panx1 channels reduces neuroinflammation and improves outcome after TBI. In addition, we found that Panx1 blockers significantly decrease ATP release and migration from activated microglia and macrophages cell lines in vitro. In the present work, we generated a microglia/macrophage Panx1 conditional knockout to examine the cell specific role of Panx1 in brain trauma. Using the murine controlled cortical impact (CCI) as a model of TBI, we found that microglia/macrophage specific Panx1 knockout reduced expression of pro-inflammatory cytokines and immune cell infiltration in CCI-injured animals when compare to flox/flox mice. Magnetic resonance imaging showed reduce blood brain barrier leakage at the injury site of CCI-injured Panx-1 knockout mice when compared to CCI-injured flox/flox mice. These results were further supported by examining biomarkers for tissue damage and blood brain barrier leakage using western blot. Finally, we showed that the conditional knockout for Panx1 mice show improved motor function after CCI with respect to CCI-injured wild type and flox/flox mice. We propose that activation of Panx1 channels in microglia/monocytes is a major contributor to the pathologies following TBI. Consequently, microglial/macrophage Pannexin-1 channels may serve as an effective therapeutic approach to improve outcome after TBI.



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