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

Abstract

28A characteristic subset of microglia expressing CD11c appears in response to brain 29 damage. However, the functional role of CD11c + microglia, as well as the mechanism of 30 its induction, are poorly understood. Here we report that the genetic ablation of signal 31 regulatory protein α (SIRPα), a membrane protein, induced CD11c + microglia in the 32 brain white matter. Mice lacking CD47, a physiological ligand of SIRPα, and 33 microglia-specific SIRPα knockout mice exhibited the same phenotype, suggesting the 34 interaction between microglial SIRPα and CD47 on neighbouring cells suppressed the 35 emergence of CD11c + microglia. A lack of SIRPα did not cause detectable damage in 36 the white matter, but resulted in the increased expression of genes characteristic of the 37 repair phase after demyelination. In addition, cuprizone-induced demyelination was 38 alleviated by the microglia-specific ablation of SIRPα. Thus, microglial SIRPα 39 suppresses the induction of CD11c + microglia that have the potential to accelerate the 40 repair of damaged white matter. 41 (Safaiyan et al., 2016). It was also shown that demyelination markedly induced CD11c + 63 microglia, even in the adult brain (Remington et al., 2007), which was suppressed in 64 mutant mice lacking Trem2 or Cx3Cr1 (Lampron et al., 2015; Poliani et al., 2015), i.e. 65 functional molecules that promote phagocytosis. Of note, the clearance of myelin debris 66 was markedly impaired in these mutant mice (Cantoni et al., 2015; Lampron et al., 67 2015; Poliani et al., 2015). CD11c + microglia also accumulate around amyloid plaques Results 94 Emergence of CD11c + microglia in the brain white matter of SIRPα-deficient mice 95To examine the role of SIRPα in microglial activation, brains of SIRPα knockout (KO) 96 mice were subjected to immunohistochemical analysis using antibodies specific to Iba1, 97 a microglia marker, and to CD68, a marker for phagocytically active microglia ( Figure 98 1A). In the brains of SIRPα KO mice, numbers of Iba1 + as well as Iba1 + /CD68 + cells 99 were significantly increased in the white matter, such as the fimbria, compared with 100 wild-type (WT) control mice, suggesting the activation of microglia in these regions 101 (Figures 1A and 1B). Activation of microglia in the white matter was similar to the 102 phenotype reported in aged mice, in which numbers of CD11c + microglia were reported 103 to be increased (Kaunzner et al., 2012). Next we examined the effect of the genetic 104 ablation of SIRPα on the expression of CD11c on microglia by using CD11c-EYFP 105 transgenic (Tg) mice (Lindquist et al., 2004), in which the expression of CD11c is 106 detected with a reporter gene. In SIRPα KO:CD11c-EYFP Tg mice, Iba1 + cells and 107 EYFP + cells were markedly increased in the white matter, including the corpus callosum, 108 external capsule, fimbria, and internal capsule, compared with control 109 SIRPα +/+ :CD11c-EYFP Tg mice (Figure 1C). Most EYFP + cells in the white matter of 110 SIRPα KO mice were Iba1 positive, suggesting th...

Heterogeneity of microglia and their differential roles in white matter pathology

“…Notably, some microglial subset can be induced by neighboring microglia. When signal regulatory protein α (SIRPα), a membrane protein, was genetically ablated, the number of CD11c + microglia was significantly increased in white matter of the brain . Microglia‐specific ablation of SIRPα alleviated cuprizone‐induced demyelination, suggesting that microglial SIRPα suppresses the induction of CD11c + microglia and demyelination damage in white matter, possibly involving indirect roles on oligodendrocyte lineage cells.…”

“…When signal regulatory protein α (SIRPα), a membrane protein, was genetically ablated, the number of CD11c + microglia was significantly increased in white matter of the brain. 96 Altogether, depending on the pathological stage of white matter damage, different subsets of microglia could affect the fate of OPCs and oligodendrocytes by secreting factors of various effects (Figure 1).…”

SIRPα on CD11c+ cells induces Th17 cell differentiation and subsequent inflammation in the CNS in experimental autoimmune encephalomyelitis

“…We recently showed that the ablation of SIRPα specifically in microglia resulted in spontaneous activation of these cells in the CNS and protection from demyelination damage [37]. However, we found that CD11c expression was not upregulated in microglia of Sirpa ΔDC mice (data not shown), indicating that SIRPα is not ablated in microglia of these mice.…”

Protective roles for myeloid cells in neuroinflammation

“…Interestingly, this subset of microglia is necessary for primary myelination and is involved in protection from EAE 16‐18 . CD11c+ microglia can be induced by CSF1R stimulation, 16 as well as by blocking Sirpα‐CD47 signalling 19 . CSF1R stimulation led to EAE suppression 16 …”