Epigenetic reprogramming of immune cells in injury, repair, and resolution

Abstract

Immune cells are pivotal in the reaction to injury, whereupon, under ideal conditions, repair and resolution phases restore homeostasis following initial acute inflammation. Immune cell activation and reprogramming require transcriptional changes that can only be initiated if epigenetic alterations occur. Recently, accelerated deciphering of epigenetic mechanisms has extended knowledge of epigenetic regulation, including long-distance chromatin remodeling, DNA methylation, posttranslational histone modifications, and involvement of small and long noncoding RNAs. Epigenetic changes have been linked to aspects of immune cell development, activation, and differentiation. Furthermore, genome-wide epigenetic landscapes have been established for some immune cells, including tissue-resident macrophages, and blood-derived cells including T cells. The epigenetic mechanisms underlying developmental steps from hematopoietic stem cells to fully differentiated immune cells led to development of epigenetic technologies and insights into general rules of epigenetic regulation. Compared with more advanced research areas, epigenetic reprogramming of immune cells in injury remains in its infancy. While the early epigenetic mechanisms supporting activation of the immune response to injury have been studied, less is known about resolution and repair phases and cell type-specific changes. We review prominent recent findings concerning injury-mediated epigenetic reprogramming, particularly in stroke and myocardial infarction. Lastly, we illustrate how single-cell technologies will be crucial to understanding epigenetic reprogramming in the complex sequential processes following injury.

Figure 1. Immune cell activation during different phases upon tissue injury.

Tissue-resident immune cells, particularly γδT cells or resident macrophages, recognize damaged cells upon injury, e.g., via the NKG2D receptor or TLRs, respectively. Activated tissue-resident cells secrete soluble factors that attract other immune cells, such as proinflammatory cytokines (TNF-α, IFN-γ, IL-6, or IL-1) together with growth factors (PDGF, VEGF, or IGF-1) that stimulate epithelial cell proliferation. CXCL8 released by tissue-resident cells in response to TLR activation attracts neutrophils, which enter the site of injury. Neutrophils produce antimicrobial molecules, cytokines, and growth factors such as VEGF-A, which recruits other inflammatory cells such as monocytes and stimulates angiogenesis and tissue cell proliferation. Recruited phagocytes clean damaged tissue debris by phagocytosis and secrete various cytokines, proteases, and growth factors promoting tissue repair. They first acquire proinflammatory function [classically activated, or M(IFN-γ), macrophages] and, when the pathogen is cleared, can be repolarized toward antiinflammatory tissue repair [alternatively activated, or M(IL-4), macrophages] in the presence of cytokines produced by type 2 immune T cells. M(IL-4) macrophages secrete arginase; the growth factors VEGF-A, PDGF, and IGF; and other molecules. In the resolution phase, regulatory T cells suppress immune response by secreting IL-10 and TGF-β. Further, lipid-derived specialized pro-resolving mediators actively promote inflammation cessation, resolution, and repair.

Figure 2. Epigenetic events in immune cells during tissue injury.

(A) Possible modes of epigenetic regulation to tune immune cell function. On the left, mechanisms of repressing transcription such as closed chromatin, DNA methylation, repressive histone marks, or inhibiting long noncoding RNAs (lncRNAs) are depicted. On the right, a locus with active transcription is depicted, including loss of DNA methylation, open chromatin structure including accessible enhancer and promoter sequences, activating histone modifications, and activating transcription factors. Different histone marks are presented as colored dots. (B) During immune cell activation, epigenetic regulation leads to activation of prior silent genes, while some homeostatic genes are turned off. Epigenetic events during homeostasis and activation of immune cells have been experimentally addressed, while elucidation of these processes during repair and resolution still needs to be resolved.

Figure 3. Integrated view of the epigenetic processes occurring over time during injury, repair, and resolution.

Epigenetic regulatory mechanisms can be studied on the level of population, individual, and tissues and organs, as well as the single-cell level. Since any injury is followed by a sequence of processes ranging from immune system activation to peak reactivity to repair and resolution, time-resolved analyses of epigenetic processes are required. At the different levels (population, individuals, tissues and organs, and single cells), different multi-omics approaches can be applied to determine epigenetic regulation. Resolution, complexity that can be determined, scalability of epigenetic assays, and costs of analyses differ substantially between the different settings. Future studies particularly targeting the repair and resolution phases will require sophisticated planning of overall goals and experiments to be performed. eQTL, expression quantitative trait loci; epiQTL, epigenetic quantitative trait loci.