Integrated Multi-Omic Analysis Reveals KDM5B as a Regulator of Microglial Reactivity to Immunomodulatory Stimuli

Microglia
maintain brain homeostasis through coordinated pathways,
including cell migration, phagocytosis, and secretion of immune-related
signaling factors. Microglial reactivity is associated with a variety
of functional outcomes that are highly context-dependent withepigenetic
regulation through DNA methylation and histone modifications implicated
in this complex control of microglial plasticity. Specifically, in
relation to histone methylation, lysine-specific demethylase 5B (KDM5B)
has been associated with several pathophysiological states, including
neurodevelopmental and inflammatory disorders, cancer, and alcohol
use disorder (AUD); however, the cell-type-specific role of KDM5B
in microglial reactivity has not been investigated. In this study,
transcriptomic and proteomic analyses were used to characterize the
effects of KDM5B depletion on microglial pathways in clustered regularly
interspaced short palindromic repeats (CRISPR)-edited adult-derived
murine microglial cells. Additionally, various immunomodulatory stimuli,
including lipopolysaccharide (LPS), interleukin-4, and alcohol, were
used to study the effects of KDM5B depletion on immune reactivity
in microglia using deep proteomics and bioinformatic analysis. Through
this comprehensive characterization, KDM5B-depleted microglia exhibited
broad remodeling of immune reactivity, including reduced intracellular
and secreted inflammatory responses to lipopolysaccharide as well
as distinct modulation of alcohol- and interleukin-4-induced pathways,
that was functionally demonstrated by altered cytokine secretion profiles.
Results from this study provide critical insight into KDM5B-mediated
immunological effects on microglial function.