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Muroy et al. Neuroimmunol Neuroinflammation 2020;7:166-82 I http://dx.doi.org/10.20517/2347-8659.2020.16 Page 167

INTRODUCTION
Microglia are the resident myeloid-lineage cells of the brain. They actively provide homeostatic surveillance
of the brain parenchyma, playing critical roles during development, maintenance, and repair throughout
the life of an organism. As innate immune cells, however, microglia are also capable of mounting a full
[1-6]

inflammatory response to environmental challenge in order to clear threats and restore homeostasis .
Microglia express pattern recognition receptors including Toll-like receptors to sense changes in their
environment, such as infection by pathogens or endogenous danger signals. They can then respond by
releasing proinflammatory mediators such as tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL-1β),
IL-6, reactive oxygen species, and reactive nitrogen species including nitric oxide (NO) to protect against
threats [1,5,7] .

Although beneficial when their production is tightly controlled, deregulated or sustained microglial
production of inflammatory mediators can lead to collateral damage of surrounding neurons and other
cells [5,7,8] . Thus, the transition to an activated state, as well as timely resolution of the inflammatory
response, must be tightly regulated. Increasing evidence suggests that, during aging, microglia lose
homeostatic function and acquire a proinflammatory phenotype that exacerbates aging-related brain
[9]
dysfunction . Indeed, aberrant microglia activation has been found in many types of age-related
neurodegenerative conditions, for example Parkinson’s disease (PD) and Alzheimer’s disease (AD), which
are marked by inflammatory processes involving glia, and microglia in particular [9-11] .

Since excessive production of proinflammatory mediators is neurotoxic [8,12-14] , various molecular
mechanisms exist to regulate transcriptional repression of inflammatory gene expression. For example,
basal state repression, that is, before the arrival of an activating signal, is generally carried out via
recruitment of co-repressor complexes that prevent initiation of inflammatory gene transcription. After
stimulation by an activating signal, additional mechanisms can maintain quiescence by restraining active
transcription. Finally, numerous mechanisms mediate the timely resolution of the inflammatory response
at the transcriptional level, including transrepression mechanisms that can remove transcription factors
from inflammatory gene promoters [8,15-18] .

Studies have also highlighted an important role for chromatin modifications in the transcriptional control
[21]
of inflammatory gene expression [19,20] . A recent study by Soreq et al. , which compared transcriptional
profiles of different brain cell types and regions throughout healthy human aging, found microglial gene
expression profiles as being one of the most predictive markers of biological age in the brain. The same
study identified a relatively unknown gene, PHD finger protein 15 (PHF15), among the top 25 differentially
expressed genes in microglia during aging. Work in embryonic stem cells, as well as sequence and
structural similarity to other members of the PHF family, indicate that PHF15 is a putative chromatin-
[22]
mediated gene regulator .
Given that aging skews microglia towards a proinflammatory phenotype, and that PHF15 was found
to be highly upregulated during non-pathological aging, we sought to determine whether Phf15 might
regulate microglial inflammatory function. We found that Phf15 strongly represses proinflammatory
gene expression, regulating both basal and signal-dependent activation and modulating the magnitude
and duration of the mouse microglial inflammatory response. Importantly, Phf15 seems to regulate
proinflammatory and interferon type I (IFN-I)-dependent gene expression. Increased IFN-I tone and
proinflammatory cytokine expression are both hallmarks of the aging brain [23-26] . Our findings suggest that
Phf15 is an important novel repressor of microglial inflammatory function that might work to counteract
age-induced inflammation in the healthy, aging brain.