Inflammatory memory and tissue adaptation in sickness and in health

Abstract

Our body has a remarkable ability to remember its past encounters with allergens, pathogens, wounds and irritants, and to react more quickly to the next experience. This accentuated sensitivity also helps us to cope with new threats. Despite maintaining a state of readiness and broadened resistance to subsequent pathogens, memories can also be maladaptive, leading to chronic inflammatory disorders and cancers. With the ever-increasing emergence of new pathogens, allergens and pollutants in our world, the urgency to unravel the molecular underpinnings of these phenomena has risen to new heights. Here we reflect on how the field of inflammatory memory has evolved, since 2007, when researchers realized that non-specific memory is contained in the nucleus and propagated at the epigenetic level. We review the flurry of recent discoveries revealing that memory is not just a privilege of the immune system but also extends to epithelia of the skin, lung, intestine and pancreas, and to neurons. Although still unfolding, epigenetic memories of inflammation have now been linked to possible brain disorders such as Alzheimer disease, and to an elevated risk of cancer. In this Review, we consider the consequences-good and bad-of these epigenetic memories and their implications for human health and disease.

Fig. 1 |. Overview of inflammatory and tissue memory.

Short-lived and long-lived cells in our tissues sense and response to inflammatory, metabolic and microbial stimuli and maintain a state of alertness even after withdrawal of the initial stimuli. Primed cells are able to respond more rapidly to secondary triggers, which provide anti-pathogen and pro-repair functions. When unchecked, these same primed cells can fuel inflammatory pathologies and give rise to cancers. HSPC, haematopoietic stem and progenitor cell; ILC, innate lymphoid cell; NK, natural killer.

Fig. 2 |. Mechanisms of memory.

Following a primary stimulus, a subset of stress-responsive loci—’memory domains’—located within distal (enhancer) regions of key inflammatory memory genes, are opened. Accessibility is made possible through stimuli-specific transcription factors (TFs) that have the ability to recognize and bind to their motifs in otherwise closed chromatin. Once the memory domain is accessible, the broad stress-responsive TF FOS, which heterodimerizes with other AP-1 family members (for example, JUN), gains access along with several homeostatic TFs that also have binding motifs within these domains. During this inflammatory phase, certain immune-priming, long non-coding RNAs (lncRNAs) are transcribed, binding to the Mediator complex (Med), which topologically brings together the stimuli-activated enhancers with their gene promoters to initiate RNA polymerase II (Pol II)-mediated transcription. Both TFs and lncRNAs can bind to and recruit histone modifiers, in particular, H3K4me1 at enhancers and H3K4me3 at promoters. Once inflammation and stress have subsided, while stimuli-specific TFs, FOS and lncRNA expression wanes, homeostatic TFs and these histone modifications keep memory-associated genes primed, but largely transcriptionally inert. In this open memory state, the TF FOS, activated by a diverse array of stresses, can then operate independently of chromatin-opening ‘pioneer-like factors’ to rapidly recall memory-associated transcription at memory-associated genes. Ac, acetylation; Me, methylation.