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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 159

of inflammasome components and response to stimulus, the dependency on caspase-1 for IL-1b secretion
is only partial and a higher level of mature IL-1b secretion is observed with longer periods of priming
than in hematopoietic macrophages. Prolonged IL-1b secretion from microglia likely occurs as a result of
a deficit in negative regulation mechanisms as compared to macrophages. As an additional consideration,
activation of the inflammasome in peripheral macrophages serves in a regulatory capacity in the induction
of pyroptotic cell death to remove the damaging immune cell. How this translates to microglia remains in
question given the long-lived nature of these cells.

CONCLUSION
The interest in metabolic functions of microglia has evolved from our knowledge of mitochondrial
demands and responses of peripheral macrophages in their various effector functions. Recent findings
have set the framework for an association between the metabolic status of immune cells with the
characteristics of an immune response against pathogens. The majority of studies have relied on different
pro-inflammatory stimuli, such as virus, GM-CSF, LPS, LPS + INFg, or IL-4, to induce cells to examine
macrophage metabolism in vitro. However, the resulting phenotype and metabolic profiles can differ with
not all stimuli leading towards glycolysis. Conversely, the diverse non-inflammatory stimuli normally
[74]
examined, i.e., IL-10, glucocorticoids, IL-13, M-CSF, and IL-4, are grouped together ; however, similar
to the pro-inflammatory stimuli, the phenotypic change may differ. This is not unexpected given that
macrophage activation states display multiple profiles depending on the initiating stimuli [206] . However,
examination of metabolic adaptations of macrophages has demonstrated that such adaptations are critical
factors regulating a variety of immune cell responses. The need to rapidly modulate cellular responses
to pathogen or inflammatory signals demands a remodeling of the metabolic pathways to execute such
actions. While many of the basic responses translate across peripheral macrophages and microglia, the
uniqueness of microglia suggests that this may not be a complete translation across cells. Additionally,
the limited range of inducing stimuli examined in microglia cells raises the question of how the cells will
compare given a broader range of stimuli. Further exploration of similarities and uniqueness will contribute
to our understanding of the interplay between metabolism and immune cell responses as they apply to
the nervous system. It may also offer a framework from which to address issues of translation between
experimental animal data to human disease conditions that involve the innate immune system [207-209] .
Understanding the mitochondrial-related characteristics of microglia will likely be critical in identifying
successful therapeutic approaches to the detrimental effects of neuroinflammation or in facilitating repair.

DECLARATIONS
Acknowledgments
The authors acknowledge Drs. Christopher McPherson, Christian Lefebvre d’Hellencourt, and Negin
Martin for providing reviewer comments on the manuscript.

Authors’ contributions
Contributed to the conceptualization, design and interpretation of the experiments and in manuscript
preparation: Childers G
Generated the original data: Lopez Hernandes I, Giridharan S
Contributed to the conceptualization of the manuscript, data interpretation, and writing of the final
manuscript: Harry GJ

Availability of data and materials
Not applicable.

Financial support and sponsorship
The research was supported by NIH intramural research funding ES021164.