Microglial SIRPα regulates the emergence of CD11c+ microglia and demyelination damage in white matter

Abstract

A characteristic subset of microglia expressing CD11c appears in response to brain damage. However, the functional role of CD11c+ microglia, as well as the mechanism of its induction, are poorly understood. Here we report that the genetic ablation of signal regulatory protein α (SIRPα), a membrane protein, induced the emergence of CD11c+ microglia in the brain white matter. Mice lacking CD47, a physiological ligand of SIRPα, and microglia-specific SIRPα-knockout mice exhibited the same phenotype, suggesting that an interaction between microglial SIRPα and CD47 on neighbouring cells suppressed the emergence of CD11c+ microglia. A lack of SIRPα did not cause detectable damage to the white matter, but resulted in the increased expression of genes whose expression is characteristic of the repair phase after demyelination. In addition, cuprizone-induced demyelination was alleviated by the microglia-specific ablation of SIRPα. Thus, microglial SIRPα suppresses the induction of CD11c+ microglia that have the potential to accelerate the repair of damaged white matter.

Protective Microglial Subset in Development, Aging, and Disease: Lessons From Transcriptomic Studies

“…at the same age, although they downregulate CX3CR1 and MERTK (77,89). CD11c expression of microglia in the white matter and caudal areas of the CNS of aged mice was also shown using immunohistochemistry (90).…”

“…Conversely, microglia expressing the CD11c+ microglia signature including Apoe, Axl, Igf1, Lyz2, Itgax, and Gpnmb were identified by single-cell transcriptomics in both deand remyelinated lesions (145). Recently, cuprizone-mediated demyelination was shown to be alleviated in mice lacking microglial SIRPα that have increased numbers of CD11c+ microglia, pointing to their protective role (89). In line with the induction of CD11c+ microglia (81), stimulation of CSF1R ameliorated cuprizone-induced demyelination (146).…”

“…Recently, the emergence of CD11c+ microglia in the adult brain has been shown to be homeostatically controlled by SIRPα/CD47 interaction. Genetic ablation of SIRPα in microglia or global lack of CD47 equally resulted in increased numbers of CD11c+ microglia, suggesting that microglial SIRPα suppresses CD11c expression in the same cells (89).…”

“…The dynamics of CD11c+ microglia seem tightly spatiotemporally regulated. They first emerge during the first postnatal week, peaking at P5 and gradually decreasing as animals age, being barely detectable in the healthy adult CNS (33-35, 42, 80, 81) to increase again in aging or disease (33,73,81,85,89). Importantly, none of the studies that have investigated induction of inflammation by means of lipopolysaccharide, poly(I:C), or other immune challenges could recapitulate the robust CD11c+ signature found in steady state and disease and injury contexts (86,88,90,124,155,156).…”

Ocular hypertension suppresses homeostatic gene expression in optic nerve head microglia of DBA/2 J mice

“…We have previously used CD11c as a marker to distinguish myeloidderived cell subtypes within the ONH; with the majority of infiltrating monocyte-like cells in the ONH being CD45 hi and CD11c + . Emerging evidence is demonstrating a role for CD11c + microglia in neurodegenerative disease progression, especially during demyelinating events [62], and with T-cell interactions in the brain [63]. Given that the ONH is unmyelinated, and that Tcell changes have not been found in the glaucomatous ONH, it is unsurprising to observe so few CD11c + microglia.…”