Sex and interferon gamma signaling regulate microglia migration in the adult mouse cortex in vivo

Abstract

Although microglia possess the unique ability to migrate, whether mobility is evident in all microglia, is sex dependent, and what molecular mechanisms drive this, is not well understood in the adult brain. Using longitudinal in vivo two-photon imaging of sparsely labeled microglia, we find a relatively small population of microglia (~5%) are mobile under normal conditions. Following injury (microbleed), the fraction of mobile microglia increased in a sex-dependent manner, with male microglia migrating significantly greater distances toward the microbleed relative to their female counterparts. To understand the signaling pathways involved, we interrogated the role of interferon gamma (IFNγ). Our data show that in male mice, stimulating microglia with IFNγ promotes migration whereas inhibiting IFNγ receptor 1 signaling inhibits them. By contrast, female microglia were generally unaffected by these manipulations. These findings highlight the diversity of microglia migratory responses to injury, its dependence on sex and the signaling mechanisms that modulate this behavior.

Microglia at the blood brain barrier in health and disease

“…The proinflammatory transcriptional shift and BBB breach prompts microglia to migrate to the area of injury. Within hours of a stroke or modeled laser-ablated vessel, microglia begin their journey toward the affected region ( Ahn et al, 2018 ; Lubart et al, 2021 ; Boghozian et al, 2023 ), which is prompted by a variety of signaling molecules, including fractalkine ( Cao et al, 2019 ) and the purine, ATP ( Davalos et al, 2005 ), extracellular peroxiredoxin (prx6) ( Kuang et al, 2014 ), several Rho guanosine triphosphate hydrolyases (GTPases), like Rac, Cdc42, and Rho ( Choi et al, 2011 ), CXCL12 ( Huang et al, 2017 ), and apoptosis signal-regulating kinase 1 (ASK1) ( Cheon et al, 2017 ). Importantly, irrespective of endothelial activation, CAMs respond to severely reduced blood flow, shifting to an activated state with morphological changes that support their migration ( Masuda et al, 2011 ).…”

Minding the Gap: Exploring Neuroinflammatory and Microglial Sex Differences in Alzheimer’s Disease

“…In fact, after immune challenge, there are sex differences in the cytokines found in the hippocampus [133] and in discrimination memory impairments [134]. Microglia migrate at sex-specific rates [120], and, after injury, microglial mobility is regulated by interferon (IFN) γ in males but not females [135]. Single-cell and bulk RNA sequencing have also provided evidence for sex-specific gene expression in human microglia [136], extending the relevance of the findings in mice to humans.…”

“…Females: more activated in cortex, hippocampus, amygdala [116] Males: more complex branching in prefrontal cortex [117] P60 Rat Females: more activated in cortex, hippocampus, amygdala [116] Mouse Females: more transcriptionally mature [127] Mouse Females: increased inflammatory gene expression [127] 2-6 months Mouse Males: IFN-dependent migration after injury [135] 12 weeks Mouse Males: express more inflammatory genesFemales: more neuroprotective [129] P90 Rat Females: more complex branching in prefrontal cortex [117] 3 months Mouse No difference in morphology in any brain, spinal cord region [122] 13 weeks Mouse Males: higher density in hippocampus, cortex, amygdalaNo difference in density in striatum, cerebellumMales: greater antigen presentation capability [120] 18 months Mouse Females: more phagocytic, reduced ability to respond to insult [137] 22-25 months Mouse Females: express more disease, senescence genes [132] 24 months Mouse Females: express more inflammatory genes [128] * E, embryonic day; and P, postnatal day.…”