Lnc-ing Trained Immunity to Chromatin Architecture

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.

Keywords: BCG—Bacille Calmette-Guérin vaccine; LncRNA—long non-coding RNA; chromatin; epigenetic memory; innate immunity; macrophages; trained immunity; transcriptional (regulation).

Figure 1

HSCs are central to the establishment of trained immunity. (A) In Kaufmann et al., BCG alters the transcriptome profile of HSC and multipotent progenitors (MPP). This leads to an increase in myelopoiesis which generates epigenetically reprogrammed monocytes and macrophages that are enhanced in their ability to resolve Mtb infection. (B) In Mitroulis et al., β-glucan induces the expansion of HSCs and MPPs. In addition, β-glucan altered IL1β and GM-CSF signaling as well as glucose and lipid metabolism in MPPs. Peripheral myeloid cells derived from β-glucan-trained progenitors were enhanced in their ability to resolve systemic inflammation.

Figure 2

IPLs are central to the establishment of trained immune responses in monocytes. (A) Innate immune cells can develop enhanced resistance upon reinfection with the same or an unrelated pathogen. H3K4me3 accumulates on the promoters of trained innate immune genes. (B) 3D chromatin topology correctly positions immune priming lncRNAs (IPLs) proximal to innate immune gene promoters. This permits IPLs to direct the WDR5/MLL1 complex across immune gene promoters to facilitate their H3K4me3 epigenetic priming. (C) β-glucan upregulates IPLs, which leads to the deposition of H3K4me3 on immune gene promoters. As a result of the persistence of H3K4me3 chromatin marks, immune genes are more robustly transcribed upon reactivation by a secondary stimulus.

Figure 3

A potential mechanism describing how HSCs and/or MPPs trained by BCG or β-glucan may transmit their epigenetic memory to myeloid cells. Upon exposure to BCG or β-glucan, HSCs and/or MPPs upregulate IPLs, which in turn leads to the accumulation of H3K4me3 marks on immune genes. This epigenetic memory is then transmitted to mature myeloid cells, leading the generation of trained monocytes and macrophages.