Epigenetic Modulators of Monocytic Function: Implication for Steady State and Disease in the CNS

Abstract

Epigenetic alterations are necessary for the establishment of functional and phenotypic diversity in the populations of immune cells of the monocytic lineage. The epigenetic status of individual genes at different time points defines their transcriptional responses throughout development and in response to environmental stimuli. Epigenetic states are defined at the level of DNA modifications, chromatin modifications, as well as at the level of RNA base changes through RNA editing. Drawing from lessons regarding the epigenome and epitranscriptome of cells of the monocytic lineage in the periphery, and from recently published RNAseq data deriving from brain-resident monocytes, we discuss the impact of modulation of these epigenetic states and how they affect processes important for the development of a healthy brain, as well as mechanisms of neurodegenerative disease and aging. An understanding of the varied brain responses and pathologies in light of these novel gene regulatory systems in monocytes will lead to important new insights in the understanding of the aging process and the treatment and diagnosis of neurodegenerative disease.

Specific and Complex Reprogramming of Cellular Metabolism in Myeloid Cells during Innate Immune Responses

“…Changes on an epigenetic level are needed to convey functional and phenotypic diversity to myeloid cells, and the epigenetic status of genes determines their transcriptional responses to subsequent environmental stimuli (Papavasiliou et al, 2015). The epigenetic profile is determined by a combination of DNA (methylation) and histone (methylation, acetylation, phosphorylation) modifications, as well as specific profiles of regulatory non-coding RNAs, which together determine and control their transcriptional profile (Papavasiliou et al, 2015). Through these mechanisms, epigenetic reprogramming of myeloid cells are key for both myeloid cell differentiation on the one hand, and for induction of innate immune memory (trained immunity) on the other hand.…”

Gene expression study in monocytes: evidence of inflammatory dysregulation in early-onset obsessive-compulsive disorder

“…Blood monocytes are among the main cells of the innate immune system and take on important roles in phagocytosis, cytokine production, and T cell activation via antigen presentation [ 23 ]. Over recent decades, attention has been devoted to the possible contribution of these cells in the development and progression of neuropsychiatric disorders because monocytes and the effectors they secrete can not only drive inflammation and cause tissue damage but also influence synaptic transmission, neural plasticity, and brain function under both physiological and pathological states [ 24 , 25 ].…”

Monocyte Transcriptional Profiling Highlights a Shift in Immune Signatures Over the Course of Illness in Schizophrenia

“…Here, these immune cells and the effectors they secrete have been shown to influence a wide range of processes including learning and memory, social behavior, and mood, under both normal physiological as well as pathological conditions (6,7). Myeloid cells such as monocytes and macrophages in particular are the subject of intense investigation as they have the capacity to drive inflammation and cause tissue damage, mediate tissue repair and secrete factors that directly or indirectly influence synaptic transmission (8,9). For example, it has been demonstrated in rodents that following immune activation inflammatory monocytes are recruited to brain borders such as the choroid plexus, and that monocytes can drive both viral-induced learning and memory deficits and stressinduced behavioral alterations (10)(11)(12).…”