Microglia are innate immune cells resident in the brain. They are broadly similar in behavior to the macrophages found elsewhere in the body, with an added portfolio of duties relating to maintenance of the synaptic connections that link neurons to form neural networks. Researchers have provided evidence for microglia to both harm and help the aging brain, with various subpopulations of microglia either acting to cause damage and dysfunction or attempting to resist that damage and dysfunction. One of the most studied aspects of microglial aging is the increase in inflammatory signaling, as microglia react to the age-damaged environment and their own internal age-related dysfunctions with maladaptive patterns of behavior. Chronic inflammation in aged brain tissue contributes to neurodegeneration, and is driven in part by microglia.
In today’s open access paper, the authors expand on recent research that points to PU.1 as a gene of interest in the regulation of microglial inflammation. A few research groups have set their sights on selective PU.1 inhibition in microglia as a potential basis for therapy, as it appears to reduce inflammation in animal studies. In this new paper, the authors report that this feature of PU.1 inhibition is actually driven by a small subpopulation of microglia that are in some way acting to regulate the behavior of other microglia. This sort of behavior is well described in the adaptive immune system – consider regulatory T cells, for example. It is interesting to see innate immune cells specializing into the regulators and the regulated in response to circumstances.
Lymphoid gene expression supports neuroprotective microglia function
Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer’s disease (AD). The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with amyloid plaques.
Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated low PU.1 expression microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load.
Our findings indicate that low-PU.1 CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.
