Abstract
Innate immune function is shaped by prior exposures in a phenomenon often referred to as ‘memory’ or ‘training’. Diverse stimuli, ranging from pathogen-associated molecules to atherogenic lipoproteins, induce long-lasting training, impacting on future responses, even to distinct stimuli. It is now recognised that epigenetic modifications in innate immune cells, and their progenitors, underpin these sustained behavioural changes, and that rewired cellular metabolism plays a key role in facilitating such epigenetic marks. Oxygen is central to cellular metabolism, and cells exposed to hypoxia undergo profound metabolic rewiring. A central effector of these responses are the hypoxia inducible factors (or HIFs), which drive transcriptional programmes aiming to adapt cellular homeostasis, such as by increasing glycolysis. These metabolic shifts indirectly promote post-translational modification of the DNA-binding histone proteins, and also of DNA itself, which are retained even after cellular oxygen tension and metabolism normalise, chronically altering DNA accessibility and utilisation. Notably, the activity of HIFs can be induced in some normoxic circumstances, indicating their broad importance to cell biology, irrespective of oxygen tension. Some HIFs are implicated in innate immune training and hypoxia is present in many disease states, yet many questions remain about the association between hypoxia and training, both in health and disease. Moreover, it is now appreciated that cellular responses to hypoxia are mediated by non-HIF pathways, suggesting that other mechanisms of training may be possible. This review sets out to define what is already known about the topic, address gaps in our knowledge, and provide recommendations for future research.
Highlights
Whilst the adaptive immune system was originally defined by its capacity to retain a specific memory of prior exposure to pathogens, accumulating evidence suggests that the innate immune system possesses a primitive non-selective form of memory
The search for how diverse training stimuli could induce sustained non-specific adaptations soon turned to epigenetics, and it became clear that the metabolic responses to primary stimuli could lead to training via epigenetic modifications [4], it is important to note that other factors, such as Cyclic adenosine monophosphate (cAMP) signalling, mediate some epigenetic responses [5]
Many uncertainties remain about the role of hypoxia signalling and hypoxia in trained immunity and this review aims to summarise existing literature, along with important unresolved or unexplored questions, with a particular focus on monocyte and macrophage biology
Summary
Whilst the adaptive immune system was originally defined by its capacity to retain a specific memory of prior exposure to pathogens, accumulating evidence suggests that the innate immune system possesses a primitive non-selective form of memory. Trained immunity can be induced by diverse stimuli (e.g. β-glucan, oxidised LDL-cholesterol, catecholamines), is retained over periods longer than the lifespan of most mature innate immune cells, and alters the innate immune response to multiple distinct secondary stimuli [2,3,4]. The search for how diverse training stimuli could induce sustained non-specific adaptations soon turned to epigenetics, and it became clear that the metabolic responses to primary stimuli could lead to training via epigenetic modifications [4], it is important to note that other factors, such as cAMP signalling, mediate some epigenetic responses [5]. Detection of β-glucan (a fungal cell wall component) by monocyte pattern recognition receptors initiates a signalling cascade via Akt and mTOR to HIF-1α (hypoxia inducible factor-1α), promoting aerobic glycolysis [4]. Many uncertainties remain about the role of hypoxia signalling and hypoxia in trained immunity and this review aims to summarise existing literature, along with important unresolved or unexplored questions, with a particular focus on monocyte and macrophage biology
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