Deficiency of complement receptors CR2/CR1 in Cr2⁻/⁻ mice reduces the extent of secondary brain damage after closed head injury.

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.

• Authors: Miriam D Neher, Megan C Rich, Chesleigh N Keene, Sebastian Weckbach, Ashley L Bolden, Justin T Losacco, Jenée Patane, Michael A Flierl, Liudmila Kulik, V Michael Holers, Philip F Stahel
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 11 Pg. 95 (May 24 2014) ISSN: 1742-2094 [Electronic] England
• PMID: 24885042 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Complement C3
• Homeodomain Proteins
• Immunoglobulin M
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Complement 3b
• Receptors, Complement 3d
• fas Receptor
• RAG-1 protein
• Phosphopyruvate Hydratase

Topics

• Animals
• Astrocytes (metabolism)
• Brain (metabolism, pathology)
• Complement C3 (metabolism)
• Craniocerebral Trauma (blood, drug therapy, pathology)
• Disease Models, Animal
• Female
• Homeodomain Proteins (genetics, metabolism)
• Immunoglobulin M (therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microglia (metabolism)
• Neurons (metabolism, pathology)
• Phosphopyruvate Hydratase (blood)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Receptors, Complement 3b (deficiency)
• Receptors, Complement 3d (deficiency, genetics, immunology)
• fas Receptor (metabolism)