Deficiency of complement receptors CR2/CR1 in Cr2 -/- mice reduces the extent of secondary brain damage after closed hea
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Neher et al. Journal of Neuroinflammation 2014, 11:95 http://www.jneuroinflammation.com/content/11/1/95
RESEARCH
JOURNAL OF NEUROINFLAMMATION
Open Access
Deficiency of complement receptors CR2/CR1 in Cr2-/- mice reduces the extent of secondary brain damage after closed head injury Miriam D Neher1, Megan C Rich1, Chesleigh N Keene1, Sebastian Weckbach1, Ashley L Bolden1, Justin T Losacco1, Jenée Patane1, Michael A Flierl1, Liudmila Kulik2, V Michael Holers2 and Philip F Stahel1,3*
Abstract Complement activation at the C3 convertase level has been associated with acute neuroinflammation and secondary brain injury after severe head trauma. The present study was designed to test the hypothesis that Cr2-/- mice, which lack the receptors CR2/CD21 and CR1/CD35 for complement C3-derived activation fragments, are protected from adverse sequelae of experimental closed head injury. Adult wild-type mice and Cr2-/- mice on a C57BL/6 genetic background were subjected to focal closed head injury using a standardized weight-drop device. Head-injured Cr2-/- mice showed significantly improved neurological outcomes for up to 72 hours after trauma and a significantly decreased post-injury mortality when compared to wild-type mice. In addition, the Cr2-/- genotype was associated with a decreased extent of neuronal cell death at seven days post-injury. Western blot analysis revealed that complement C3 levels were reduced in the injured brain hemispheres of Cr2-/- mice, whereas plasma C3 levels remained unchanged, compared to wild-type mice. Finally, head-injured Cr2-/- had an attenuated extent of post-injury C3 tissue deposition, decreased astrocytosis and microglial activation, and attenuated immunoglobulin M deposition in injured brains compared to wild-type mice. Targeting of these receptors for complement C3 fragments (CR2/CR1) may represent a promising future approach for therapeutic immunomodulation after traumatic brain injury. Keywords: Closed head injury, Neuroinflammation, Complement receptor, Cr2-/- mice, Secondary brain injury
Introduction Traumatic brain injury (TBI) is considered an ‘immunological disease’ due to the significant posttraumatic alterations in host-mediated immune functions in the central nervous system (CNS) and in the periphery [1-3]. The complement system has been implicated in the acute inflammatory pathophysiology of severe brain injury by mediating blood-brain barrier (BBB) breakdown, cerebral edema, and delayed neuronal cell death [4-6]. Complement C3 represents the central molecule of the complement cascade at the point where the three main initiation pathways (classical, alternative, and lectin) merge * Correspondence: [email protected] 1 Department of Orthopedic Surgery, Denver Health Medical Center, University of Colorado School of Medicine, 777 Bannock Street, Denver, CO 80204, USA 3 Department of Neurosurgery, Denver Health Medical Center, University of Colorado School of Medicine, 777 Bannock Street, Denver, CO 80204, USA Full list of author information is available at the end of the
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