Generation of complement component C5a by ischemic neurons promotes neuronal apoptosis

C5a receptors are found in the central nervous system (CNS), on both neurons and glia. However, the origin of the C5a, which activates these receptors, is unclear. In the present study, we show that primary cultured mouse cortical neurons constitutively express C5, the precursor of C5a, and express...

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Published in:The FASEB journal 2012-09, Vol.26 (9), p.3680-3690
Main Authors: Pavlovski, Dale, Thundyil, John, Monk, Peter N., Wetsel, Rick A., Taylor, Stephen M., Woodruff, Trent M.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Brain Ischemia - metabolism
Brain Ischemia - pathology
cell death
Cell Line, Tumor
Complement C5a - biosynthesis
Enzyme-Linked Immunosorbent Assay
Female
Humans
innate immune system
Mice
Mice, Inbred C57BL
Mice, Knockout
neurodegeneration
neuroinflammation
Neurons - metabolism
Neurons - pathology
Polymerase Chain Reaction
Pregnancy
Receptor, Anaphylatoxin C5a - genetics
stroke
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Summary:C5a receptors are found in the central nervous system (CNS), on both neurons and glia. However, the origin of the C5a, which activates these receptors, is unclear. In the present study, we show that primary cultured mouse cortical neurons constitutively express C5, the precursor of C5a, and express the classical receptor for C5a, CD88. With cell ischemia caused by 12 h glucose deprivation, or oxygen‐glucose deprivation (OGD), neurons demonstrated increased apoptosis, up‐regulation of CD88, and increased levels of C5a in the media. Exogenous murine C5a (100 nM) added to the neuronal cultures resulted in apoptosis, without affecting cell necrosis. Pretreatment of the cells with the specific CD88 receptor antagonist PMX53 (100 nM) significantly blocked ischemia‐induced apoptosis (~50%), and neurons from CD88–/– mice were similarly protected. In a murine model of stroke, using middle cerebral artery occlusion (MCAO), we found that C5a levels in the brain increased; this also occurred in cerebral slice cultures exposed to OGD. CD88–/– mice subjected to MCAO had significantly reduced infarct volumes and improved neurological scores. Taken together, our results demonstrate that neurons in the CNS have the capability to generate C5a following ischemic stress, and this has the potential to activate their C5a receptors, with deleterious consequences.—Pavlovski, D., Thundyil, J., Monk, P. N., Wetsel, R. A., Taylor, S. M., Woodruff, T. M. Generation of complement component C5a by ischemic neurons promotes neuronal apoptosis. FASEB J. 26, 3680–3690 (2012). www.fasebj.org
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.11-202382