Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity

Hanamsagar, Richa; Alter, Mark D.; Block, Carina S.; Sullivan, Haley K.; Bolton, Jessica L.; Bilbo, Staci D.

doi:10.1002/glia.23277

Cited by 172 publications

(70 citation statements)

References 34 publications

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“…A similar sex-biased depletion efficacy upon PLX3397 treatment in the murine cortex has recently been reported to be independent of pharmacokinetic concentrations of the drug in the brain [ 15 ]. This is in line with various studies reporting remarkable sex differences in microglia regarding key cellular functions as well as transcriptome and proteome profiles in health and disease [ 14 , 29 , 31 , 45 , 55 , 64 , 69 – 71 ]. These findings are getting more attention recently because of the well-documented sex-related susceptibility to psychiatric and neurological diseases, in which neuroinflammation is a common denominator [ 39 , 40 , 59 ].…”

Section: Discussionsupporting

confidence: 91%

Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

Berve

West²,

Martini

et al. 2020

J Neuroinflammation

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Background The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1−/−) mice, a model of the infantile form of the diseases (CLN1). Therefore, we here explore whether pharmacological targeting of innate immune cells modifies disease outcome in CLN1 mice. Methods We applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry. Results We show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1−/− mice regarding some histopathological and clinical readouts and reflects heterogeneity of innate immune reactions in the diseased CNS. Conclusions Our results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.

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Section: Discussionsupporting

confidence: 91%

Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

Berve

West²,

Martini

et al. 2020

J Neuroinflammation

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“…6c right bottom; Supplementary Data 3) and found to be enriched for epithelial–mesenchymal transition (hypergeometric test, FDR < 0.05; Supplementary Table 6). Though the overlap of the microglia SDEGs with previous male and female microglia comparisons 33,41 was not significant, the overall result that female microglia are in a more immune-activated state was the same. Therefore, we conclude that the transcriptional differences between sexes appear in macrophages from the three tissues tested but that the specific differentially expressed genes are mostly tissue dependent.…”

Section: Resultscontrasting

confidence: 50%

“…Several previous studies have demonstrated sexual dimorphism in innate immunity mainly at the phenotypic level 59 . However, to the best of our knowledge, at the transcriptomic level of immune cells, only male and female microglia have been compared, showing that female microglia are in a more immune-activated state 33,41 . The numbers of male–female differentially expressed genes found in splenic MF and microglia were even higher than those in PC-MFs, but the identity of those genes was mostly tissue specific.…”

Section: Discussionmentioning

confidence: 99%

ImmGen report: sexual dimorphism in the immune system transcriptome

et al. 2019

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Sexual dimorphism in the mammalian immune system is manifested as more frequent and severe infectious diseases in males and, on the other hand, higher rates of autoimmune disease in females, yet insights underlying those differences are still lacking. Here we characterize sex differences in the immune system by RNA and ATAC sequence profiling of untreated and interferon-induced immune cell types in male and female mice. We detect very few differentially expressed genes between male and female immune cells except in macrophages from three different tissues. Accordingly, very few genomic regions display differences in accessibility between sexes. Transcriptional sexual dimorphism in macrophages is mediated by genes of innate immune pathways, and increases after interferon stimulation. Thus, the stronger immune response of females may be due to more activated innate immune pathways prior to pathogen invasion.

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“…Sex-dependent differences in gene expression pattern become noticeable as early as embryonic phase two, although they are not fully displayed morphologically at this time [48,49]. A recently introduced microglia-specific developmental index, based on global gene expression patterns, showed accelerated microglial development in female compared to male mouse brains [50]. In utero, environmental factors can affect microglia development in a sex-dependent manner, and for example, germ-free conditions of the mother were recently shown to impair microglia maturation to a higher extent in male compared to female fetuses [48].…”

Section: Effects Of Sex On Glial Cell Developmentmentioning

confidence: 99%

Sex-Dependent Effects of Perinatal Inflammation on the Brain: Implication for Neuro-Psychiatric Disorders

Ardalan

Chumak

Vexler

et al. 2019

IJMS

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Individuals born preterm have higher rates of neurodevelopmental disorders such as schizophrenia, autistic spectrum, and attention deficit/hyperactivity disorders. These conditions are often sexually dimorphic and with different developmental trajectories. The etiology is likely multifactorial, however, infections both during pregnancy and in childhood have emerged as important risk factors. The association between sex- and age-dependent vulnerability to neuropsychiatric disorders has been suggested to relate to immune activation in the brain, including complex interactions between sex hormones, brain transcriptome, activation of glia cells, and cytokine production. Here, we will review sex-dependent effects on brain development, including glia cells, both under normal physiological conditions and following perinatal inflammation. Emphasis will be given to sex-dependent effects on brain regions which play a role in neuropsychiatric disorders and inflammatory reactions that may underlie early-life programming of neurobehavioral disturbances later in life.

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Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity

Abstract: The above referenced article was published with an incorrect image and legend for

Cited by 172 publications

References 34 publications

Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice

ImmGen report: sexual dimorphism in the immune system transcriptome

Sex-Dependent Effects of Perinatal Inflammation on the Brain: Implication for Neuro-Psychiatric Disorders

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