Complement factor H, a marker of self protects against experimental autoimmune encephalomyelitis.
The CNS innate immune response is a "double-edged sword" representing a fine balance between protective antipathogen responses and detrimental neurocytotoxic effects. Hence, it is important to identify the key regulatory mechanisms involved in the control of CNS innate immunity and which could be harnessed to explore novel therapeutic avenues. In analogy to the newly described neuroimmune regulatory proteins also known as "don't eat me" signals (CD200, CD47, CD22, fractalkine, semaphorins), we herein identify the key role of complement regulator factor H (fH) in controlling neuroinflammation initiated in an acute mouse model of Ab-dependent experimental autoimmune encephalomyelitis. Mouse fH was found to be abundantly expressed by primary cultured neurons and neuronal cell lines (N1E115 and Neuro2a) at a level comparable to BV2 microglia and CLTT astrocytes. Mouse neurons expressed other complement regulators crry and low levels of CD55. In the brain, the expression of fH was localized to neuronal bodies and axons, endothelial cells, microglia but not oligodendrocytes and myelin sheaths and was dramatically reduced in inflammatory experimental autoimmune encephalomyelitis settings. When exogenous human fH was administered to disease Ab-dependent experimental autoimmune encephalomyelitis animals, there was a significant decrease in clinical score, inflammation, and demyelination, as compared with PBS-injected animals. We found that the accumulation of human fH in the brain parenchyma protected neurons from complement opsonization, axonal injury, and leukocyte infiltration. Our data argue for a key regulatory activity of fH in neuroprotection and provide novel therapeutic avenues for CNS chronic inflammatory diseases.
Griffiths
Mark R
MR
Department of Medical Biochemistry, Cardiff University, United Kingdom.
Neal
Jim W
JW
Fontaine
Marc
M
Das
Trina
T
Gasque
Philippe
P
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000276:immunology* / Q000378:metabolism; D017242:Complement Factor H / Q000276:immunology* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000276:immunology* / Q000378:metabolism
D017242:Complement Factor H