RGD Reference Report - Myelin down-regulates myelin phagocytosis by microglia and macrophages through interactions between CD47 on myelin and SIRPa (signal regulatory protein-a) on phagocytes. - Rat Genome Database

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Myelin down-regulates myelin phagocytosis by microglia and macrophages through interactions between CD47 on myelin and SIRPa (signal regulatory protein-a) on phagocytes.

Authors: Gitik, Miri  Liraz-Zaltsman, Sigal  Oldenborg, Per-Arne  Reichert, Fanny  Rotshenker, Shlomo 
Citation: Gitik M, etal., J Neuroinflammation. 2011 Mar 15;8:24. doi: 10.1186/1742-2094-8-24.
RGD ID: 13792533
Pubmed: PMID:21401967   (View Abstract at PubMed)
PMCID: PMC3068094   (View Article at PubMed Central)
DOI: DOI:10.1186/1742-2094-8-24   (Journal Full-text)


BACKGROUND: Traumatic injury to axons produces breakdown of axons and myelin at the site of the lesion and then further distal to this where Wallerian degeneration develops. The rapid removal of degenerated myelin by phagocytosis is advantageous for repair since molecules in myelin impede regeneration of severed axons. Thus, revealing mechanisms that regulate myelin phagocytosis by macrophages and microglia is important. We hypothesize that myelin regulates its own phagocytosis by simultaneous activation and down-regulation of microglial and macrophage responses. Activation follows myelin binding to receptors that mediate its phagocytosis (e.g. complement receptor-3), which has been previously studied. Down-regulation, which we test here, follows binding of myelin CD47 to the immune inhibitory receptor SIRPα (signal regulatory protein-α) on macrophages and microglia.
METHODS: CD47 and SIRPα expression was studied by confocal immunofluorescence microscopy, and myelin phagocytosis by ELISA.
RESULTS: We first document that myelin, oligodendrocytes and Schwann cells express CD47 without SIRPα and further confirm that microglia and macrophages express both CD47 and SIRPα. Thus, CD47 on myelin can bind to and subsequently activate SIRPα on phagocytes, a prerequisite for CD47/SIRPα-dependent down-regulation of CD47+/+ myelin phagocytosis by itself. We then demonstrate that phagocytosis of CD47+/+ myelin is augmented when binding between myelin CD47 and SIRPα on phagocytes is blocked by mAbs against CD47 and SIRPα, indicating that down-regulation of phagocytosis indeed depends on CD47-SIRPα binding. Further, phagocytosis in serum-free medium of CD47+/+ myelin is augmented after knocking down SIRPα levels (SIRPα-KD) in phagocytes by lentiviral infection with SIRPα-shRNA, whereas phagocytosis of myelin that lacks CD47 (CD47-/-) is not. Thus, myelin CD47 produces SIRPα-dependent down-regulation of CD47+/+ myelin phagocytosis in phagocytes. Unexpectedly, phagocytosis of CD47-/- myelin by SIRPα-KD phagocytes, which is not altered from normal when tested in serum-free medium, is augmented when serum is present. Therefore, both myelin CD47 and serum may each promote SIRPα-dependent down-regulation of myelin phagocytosis irrespective of the other.
CONCLUSIONS: Myelin down-regulates its own phagocytosis through CD47-SIRPα interactions. It may further be argued that CD47 functions normally as a marker of "self" that helps protect intact myelin and myelin-forming oligodendrocytes and Schwann cells from activated microglia and macrophages. However, the very same mechanism that impedes phagocytosis may turn disadvantageous when rapid clearance of degenerated myelin is helpful.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of phagocytosis involved_inIMP 13792533; 13792533PMID:21401967ARUK-UCL 
regulation of Fc receptor mediated stimulatory signaling pathway involved_inIMP 13792533PMID:21401967ARUK-UCL 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cell surface located_inIDA 13792533; 13792533; 13792533; 13792533PMID:21401967ARUK-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Cd47  (Cd47 molecule)
Lgals3  (galectin 3)
Mbp  (myelin basic protein)
Sirpa  (signal-regulatory protein alpha)


Additional Information