. Sex-Specific Features of Microglia from Adult Mice. Cell Rep. 2018 Jun 19;23(12):3501-3511. PubMed.


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  1. This paper adds another interesting set of data to the growing list of features attributed to microglia.

    The identification of a sex-specific microglia signature in the healthy adult brain should be carefully considered when designing experiments in mice, especially when inflammatory parameters may be involved such as in neurodegenerative or neuroinflammatory diseases. The expression profile of male microglia confer a significantly increased inflammatory predisposition, which was studied in vivo and in vitro in the manuscript. It would be interesting to investigate if this characteristic is also valid in human microglia cells. The sex-specific gene sets that were identified in the study are not directly linked to gene sets that we identified as upregulated in inflammation or neurodegeneration. Therefore, it would be especially interesting to determine the function of the significantly altered sex-specific genes, and if there is a minimal requirement of genes that can switch the sex of microglia in one or the other direction. Alternatively, the sex differences might be determined by epigenetic programming, since the profiles identified seem to be rather cell intrinsic, probably determined very early in life, stable, and not determined by environmental cues. It would be very interesting to investigate how these differences are generated in microglia.

    A second novelty of the manuscript is the grafting of microglia into the brain via intra-nasal administration. Here, I would have loved to get more data on the basic details of the grafting, for example, immunohistochemistry with microglial homeostasis markers such as TMEM119 or P2ry12. We showed that the latter are quickly downregulated in the diseased brain or after phagocytosis.

    I would also be interested to see what happened to the endogenous microglia that usually also start to appear again after CSF-1R inhibition is stopped, and that would easily outnumber the grafted cells. This fact was neglected in the manuscript. Recent investigations showed that depletion of microglia from the brain by CSF-1R inhibition facilitates engraftment of macrophages to the brain (Cronk et al., 2018). Therefore, the phenotype seen by Villa et al. might also be influenced by peripheral immune cells. This should be investigated in more detail in the future.

    However, this grafting model might be informative in studying microglia sex differences in neurodegenerative diseases and how their basic expression profiles might influence the phenotype switch toward the neurodegenerative microglia we identified in disease. In SOD1 mice, the mouse model for amyotrophic lateral sclerosis, the microglia homeostatic profile is lost much faster in male mice (Butovsky et al., 2015). We did not perform RNAseq at this time, but only measured microglia-specific genes. It would be interesting to see if and how the basic expression profile of male microglia might contribute to the accelerated disease phenotype. Here, grafting of female microglia into male mice would be very informative.


    . Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia. J Exp Med. 2018 Jun 4;215(6):1627-1647. Epub 2018 Apr 11 PubMed.

    . Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann Neurol. 2015 Jan;77(1):75-99. Epub 2014 Nov 27 PubMed.

    View all comments by Susanne Krasemann
  2. The paper by Maggi and colleagues shows that microglia acquire a gender bias early on, which is maintained in the adult. A really cool experiment they do is to transplant trans-nasally male or female microglia, and to demonstrate in a model of ischemia that female microglia are more neuroprotective.

    The paper is of interest as it could contribute to an explanation of differential susceptibility of men and women to certain neurological diseases.

    In the paper, microglia are often identified using markers that have low levels of expression. In future studies, it would be important to use markers that are highly expressed in microglia and are known to distinguish homeostatic versus disease-associated microglia. This is not a major critique, but it is important to corroborate the findings using validated microglia markers that may also have functional significance.

    View all comments by Marco Colonna
  3. Excellent comment. Indeed, this is what we are doing at present time. Our first effort was to evaluate the extent to which the microglial sex difference has a functional significance; now that we have demonstrated this for an acute event, we are interested in continuing in chronic inflammatory diseses such as neurodegenerative disorders.

    View all comments by Adriana Maggi

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  1. Girl Power? In Mice, Female Microglia Protect Against Ischemic Injury