A P Coulibaly1, W T Gartman2, V Swank3, J A Gomes4, L Ruozhuo5, J DeBacker6, J J Provencio7. 1. Department of Neurology and Neuroscience, University of Virginia, PO Box 800394, Charlottesville, VA, 22908, USA. 2. University of North Carolina, Chapel Hill, NC, USA. 3. Neuroscience, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA. 4. Cerebrovascular Center, Cleveland Clinic, Cleveland, OH, USA. 5. Department of Neurology, Chinese PLA General Hospital, Beijing, China. 6. Department of Anesthesiology, University of Toronto, Ontario, CA, USA. 7. Department of Neurology and Neuroscience, University of Virginia, PO Box 800394, Charlottesville, VA, 22908, USA. Jp3b@virginia.edu.
Abstract
BACKGROUND: How inflammatory cells are recruited into the central nervous system is a topic of interest in a number of neurological injuries. In aneurysmal subarachnoid hemorrhage (SAH), neutrophil accumulation in the central nervous system 3 days after the hemorrhage is a critical step in the development of delayed cerebral injury (DCI). The mechanism by which neutrophils enter the central nervous system is still unclear. METHODS AND RESULTS: To identify human effectors of neutrophil recruitment, cerebrospinal fluid (CSF) samples were taken from a small, selected sample of SAH patients with external ventricular drainage devices (10 patients). Among a battery of CSF cytokines tested 3 days after SAH, five cytokines were associated with poor 90-day outcome (modified Rankin Score 3-6). A parallel study in a mouse model of mild SAH showed elevation in three cytokines in the CNS compared to sham. IL-17 and IL-2 were increased in both patients and the mouse model. IL-17 was investigated further because of its known role in neutrophil recruitment. Inhibition of RAR-Related Orphan Receptor Gamma T, the master transcription factor of IL-17, with the inverse agonist GSK805 suppressed neutrophils entry into the CNS after SAH compared to control. Using an IL-17 reporter mouse, we investigated the source of IL-17 and found that myeloid cells were a common IL-17-producing cell type in the meninges after SAH, suggesting an autocrine role for neutrophil recruitment. CONCLUSIONS: Taken together, IL-17 appears to be in important factor in the recruitment of neutrophils into the meninges after SAH and could be an important target for therapies to ameliorate DCI.
BACKGROUND: How inflammatory cells are recruited into the central nervous system is a topic of interest in a number of neurological injuries. In aneurysmal subarachnoid hemorrhage (SAH), neutrophil accumulation in the central nervous system 3 days after the hemorrhage is a critical step in the development of delayed cerebral injury (DCI). The mechanism by which neutrophils enter the central nervous system is still unclear. METHODS AND RESULTS: To identify human effectors of neutrophil recruitment, cerebrospinal fluid (CSF) samples were taken from a small, selected sample of SAHpatients with external ventricular drainage devices (10 patients). Among a battery of CSF cytokines tested 3 days after SAH, five cytokines were associated with poor 90-day outcome (modified Rankin Score 3-6). A parallel study in a mouse model of mild SAH showed elevation in three cytokines in the CNS compared to sham. IL-17 and IL-2 were increased in both patients and the mouse model. IL-17 was investigated further because of its known role in neutrophil recruitment. Inhibition of RAR-Related Orphan Receptor Gamma T, the master transcription factor of IL-17, with the inverse agonist GSK805 suppressed neutrophils entry into the CNS after SAH compared to control. Using an IL-17 reporter mouse, we investigated the source of IL-17 and found that myeloid cells were a common IL-17-producing cell type in the meninges after SAH, suggesting an autocrine role for neutrophil recruitment. CONCLUSIONS: Taken together, IL-17 appears to be in important factor in the recruitment of neutrophils into the meninges after SAH and could be an important target for therapies to ameliorate DCI.
Authors: Jose Javier Provencio; Valerie Swank; Haiyan Lu; Sylvain Brunet; Selva Baltan; Rohini V Khapre; Himabindu Seerapu; Olga N Kokiko-Cochran; Bruce T Lamb; Richard M Ransohoff Journal: Brain Behav Immun Date: 2016-02-09 Impact factor: 7.217
Authors: Michael N Diringer; Thomas P Bleck; J Claude Hemphill; David Menon; Lori Shutter; Paul Vespa; Nicolas Bruder; E Sander Connolly; Giuseppe Citerio; Daryl Gress; Daniel Hänggi; Brian L Hoh; Giuseppe Lanzino; Peter Le Roux; Alejandro Rabinstein; Erich Schmutzhard; Nino Stocchetti; Jose I Suarez; Miriam Treggiari; Ming-Yuan Tseng; Mervyn D I Vergouwen; Stefan Wolf; Gregory Zipfel Journal: Neurocrit Care Date: 2011-09 Impact factor: 3.210
Authors: Aminata P Coulibaly; Pinar Pezuk; Paul Varghese; William Gartman; Danielle Triebwasser; Joshua A Kulas; Lei Liu; Mariam Syed; Petr Tvrdik; Heather Ferris; J Javier Provencio Journal: Stroke Date: 2021-08-18 Impact factor: 10.170