Abstract
Human innate immune cells exposed to certain infections or stimuli develop enhanced immune responses upon re-infection with a different second stimulus, a process termed trained immunity. Recent studies have revealed that hematopoietic stem cells (HSCs) are integral to trained immune responses as they are able to “remember” transcriptional responses and transmit this state to their progeny to educate them how to respond to future infections. The macrophages that arise from trained HSCs are epigenetically reprogrammed and as a result robustly express immune genes, enhancing their capability to resolve infection. Accumulation of H3K4me3 epigenetic marks on multiple immune gene promoters underlie robust transcriptional responses during trained immune responses. However, the mechanism underpinning how these epigenetic marks accumulate at discrete immune gene loci has been poorly understood. In this review, we discuss the previously unexplored contributions of nuclear architecture and long non-coding RNAs on H3K4me3 promoter priming in trained immunity. Altering the activity of these lncRNAs presents a promising therapeutic approach to achieve immunomodulation in inflammatory disease states.
Highlights
Reviewed by: Girdhari Lal, National Centre for Cell Science (NCCS), India Jingying Zhou, The Chinese University of Hong Kong, China
These early observations are strongly supported by more recent studies which show that monocytes and macrophages pre-exposed to certain stimuli (e.g., β-glucan) prior to exposure to certain infectious agents, acquired a memory of this exposure leading to enhanced resistance upon reinfection with a second infectious agent (Kleinnijenhuis et al, 2012; Quintin et al, 2012; Saeed et al, 2014; Netea et al, 2016)
The enhanced immunity observed in trained monocytes and macrophages is driven by epigenetic modifications that modulate the expression of innate immune genes (Quintin et al, 2012)
Summary
Bone marrow-derived macrophages (BMDMs) derived from BCG vaccinated mice have been shown to exist in an epigenetically primed state prior to Mtb infection, and possess. An enhanced ability to control Mtb infection (Kaufmann et al, 2018) This implies that HSCs or MPPs may be epigenetically reprogrammed by BCG, and this altered epigenetic state is transmitted to their progeny. The generation of immune memory in tissue-resident innate immune cells is poorly investigated, a recent study revealed that AM develop innate immune memory which protects the host from a subsequent lethal dose of pneumonia (Yao et al, 2018). This occurred in a manner that did not involve bone marrow progenitors or circulating monocytes (Yao et al, 2018). As NeST is a WDR5interacting lncRNA that is induced by IFNγ (Gomez et al, 2013), it is possible that IFNγ-dependent signaling activates an entirely new set of lncRNAs with “IPL-like” properties
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