. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature. 2019 Apr;568(7751):187-192. Epub 2019 Apr 3 PubMed.


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  1. Pluvinage et al. elucidate previously unappreciated roles for CD22 in the aging brain. Comparing young and old mice, the group of Tony Wyss-Coray observed that CD22 is increased in microglia during aging. This observation was rather unexpected as CD22 is an inhibitory molecule mainly known to “dampen” the activation of B-lymphocytes.

    Using advanced techniques of genetic engineering, the authors have shown that the age-dependent increase of CD22 in microglia correlates with a reduced phagocytic activity of these cells, resulting in accumulation of cellular debris and protein aggregates, which normally accumulate in the senile brain. It is remarkable that administration of a CD22 blocker in the brains of aged mice boosts the phagocytic function of microglia. Microglia could more efficiently remove both cellular debris and Aβ aggregates injected into the mouse brain. Importantly, the cognitive skills of old mice receiving the CD22 blocker, but not the placebo, were significantly improved.

    These findings may soon pave the way for therapeutic applications in humans, especially for the treatment of age-related diseases such as Alzheimer’s.

    View all comments by Simone Brioschi
  2. New work from the Wyss-Coray lab reports that CD22 plays a role in regulating the phagocytic capacity of microglia. This is a compelling paper that adds depth to our understanding of the intricate mechanisms that act to regulate microglial actions. CD22 is principally expressed on B cells, thus its appearance on aged microglia is unexpected, although several recent RNA-Seq studies revealed its presence in the brain in other disease settings. The selective expression of CD22 as a function of aging provides a new and important example of how the aging brain employs sophisticated mechanisms to calibrate its capacity to perform tissue maintenance and constrain microglial responses to a progressively more proinflammatory brain microenvironment. CD22 has been described to act broadly to inhibit B-cell receptor signaling and although the present study is focused on phagocytosis, it is likely to have broader roles in suppressing microglial activation given the mechanisms through which it acts intracellularly.

    It is interesting that a screen for modifiers of phagocytosis turned up CD22 in microglia. It should be noted their assay involved phagocytosis of fluorescent beads, which are taken up through fluid phase phagocytic mechanisms largely related to process extension and retraction. An analogous CRISPR screen of phagocytic regulators employed a rather different strategy and was designed to screen cargo-driven phagocytic mechanisms in myeloid cells (Haney et al., 2018). Interestingly, this screen also picked up genes associated with sialic acid moieties that were linked to suppression of phagocytosis.

    One of the most intriguing outcomes is the capacity of CD22-null mice or those receiving anti-CD22 antibodies to perform better in several behavioral assays. These data serve to reinforce the idea that the modulation of the innate immune system in the brain plays critical roles in cognition in aging and dementia and may be amenable to therapeutic intervention.

     Overall, this is a persuasive and impressive body of work, elegantly done.

    View all comments by Gary Landreth

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  1. CD22 Suppresses Microglial Phagocytosis—A New Therapeutic Target?