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Harry et al. Neuroimmunol Neuroinflammation 2020;7:150-65 I http://dx.doi.org/10.20517/2347-8659.2020.07 Page 151

INTRODUCTION
The function of innate immune cells such as macrophages is to recognize and respond to a novel stimulus
including microbial pathogens and sterile activators. These pro- and anti-inflammatory responses are major
sources of soluble molecules, cytokines, hormones, and neuropeptides These factors provide tools to sense,
process, and relay physiological signals beyond their canonical roles. Macrophages display a heterogeneous
repertoire to fulfill a broad range of functions in host defense, including tissue homeostasis and repair,
pathology, and development. To accomplish this, innate immune cells adopt various activation phenotypes.
Precise regulation of such activation is essential for maintenance of tissue homeostasis with governance
accomplished by a balance of stimulatory and inhibitory signals. Multiple lines of evidence suggest an
interlinked relationship between innate immunity and the integrity and function of mitochondria serving
to maintain this homeostatic balance. Metabolic pathways provide the necessary energy and serve to
regulate phenotype and function. Pro-inflammatory macrophages {M[LPS(+IFNg)]} display an enhanced
glycolytic metabolism and impaired mitochondrial oxidative phosphorylation (OXPHOS). These energy
shifts place mitochondria in a pivotal signaling role in macrophage response to stimuli and circumventing
[1-3]
immune checkpoint signals . The link between immunological and metabolic processes associated with
mitochondria, immunometabolism, may influence activation states and polarization of myeloid cells to
[4-7]
fine-tune their functions .

Of the specialized cells of the central nervous system (CNS), basic host defense mechanisms exist
predominantly in microglia as resident macrophages. Microglia share many phenotypic characteristics
with peripheral macrophages yet are unique in their origin and molecular or transcriptional profile [8-15] .
The available literature on the immunometabolism of microglia, as compared to what is known of
peripheral macrophages, is limited but growing to address questions of similarities and differences [6,16] .
It may also allow for a framework to understand the various other tasks undertaken by microglia during
development and chronic maintenance. Here, we present a summary of how these dynamics characterized
in peripheral macrophages are displayed in microglia. While much of this work is still somewhat under a
“work in progress” classification, even in the peripheral macrophage, new insights provided by an increased
understanding of metabolic reprogramming foster a better understanding of macrophage and microglia
regulation and function.

MICROGLIA AND IMMUNE CELLS IN THE CNS
The mechanical separation of the CNS from the circulation by the blood-brain barrier [17,18] influences
immune responses [19,20] by excluding many peripherally derived innate and adaptive immune cells and
[21]
inflammatory molecules . However, infiltrating cells significantly contribute to any neuroinflammatory
response following disruption of the blood-brain barrier, as can occur with physical injury or high levels
of inflammation. In such cases, blood-borne monocytes are allowed to enter the brain parenchyma and,
over time, can transition and assume a brain-specific phenotype [22-24] . Additionally, with a T cell-mediated
neuroinflammation, peripheral innate immune cells enter the brain as a protective host defense against
infection and facilitate repair following stroke or physical trauma [25,26] . In such a case, interactions between
microglia and T cells can be signaled via interleukin (IL)-23 and IL-1b, leading to the production of
granulocyte-macrophage colony-stimulating factor (GM-CSF) to facilitate microglia proliferation in a
[27]
manner to promote an appropriate level of response to injury . Recently, the identification of innate
lymphoid cells in the brain suggests an additional innate immune cell population that may act to control
neuroinflammation . Thus, in such conditions, the macrophage population likely represents a combination
[28]
of resident microglia and infiltrating monocytes. As a distinction between these two populations, it has
been suggested that resident microglia focus on tasks related to maintaining tissue homeostasis while
infiltrating cells are involved in severe inflammatory injuries [29,30] .