Immunometabolic Crosstalk: An Ancestral Principle of Trained Immunity?

Abstract

Memory was traditionally considered an exclusive hallmark of adaptive immunity. This dogma was challenged by recent reports that myeloid cells can retain 'memory' of earlier challenges, enabling them to respond strongly to a secondary stimulus. This process, designated 'trained immunity', is initiated by modulation of precursors of myeloid cells in the bone marrow. The ancestral innate immune system of lower organisms (e.g., Caenorhabditis elegans) can build long-lasting memory that modifies responses to secondary pathogen encounters. We posit that changes in cellular metabolism may be a common denominator of innate immune memory from lower animals to mammals. We discuss evidence from C. elegans and murine/human systems supporting the concept of an ancestral principle regulating innate immune memory by controlling cellular metabolism.

Figure 1.. Trained immunity in human monocytes.

β-Glucan or BCG can lead to immune-metabolic changes in human monocytes, particularly the induction of glycolysis, glutaminolysis and cholesterol metabolism. The generation of metabolic intermediates, including acetyl-CoA, fumarate or mevalonate, can induce epigenetic alterations that drive innate immune memory, thereby improving the response of monocytes to secondary infectious stimuli.

Figure 2.. Trained immunity in HSPCs in mice.

Western-type diet and microbe-derived stimuli (e.g. β-glucan) linked to trained immunity can induce the upregulation of pro-inflammatory cytokines, such as IL-1β, which trigger metabolic changes, particularly alterations in glucose and lipid metabolism in HSPCs. Cholesterol accumulation in HSPCs, for instance due to its increased biosynthesis or due to decreased cholesterol efflux through exporters such as ABCA1 or ABCG1, can drive myeloid differentiation bias. These alterations in HSPCs associated with trained immunity can mediate on the one hand, a hematopoietic improved response to chemotherapy, and on the other hand, may promote atherosclerosis and cardiovascular inflammation.

Figure 3.. Putative insulin signaling-mediated immunometabolic crosstalk in C. elegans.

A complex organismal response to infection involves processes such as pathogen recognition, neuro-endocrine signaling, and general stress responses. Such processes trigger signaling cascades that converge to activate DAF-16/FoxO in effector cells (e.g. intestinal cells and neurons), although the exact mechanisms are unknown. The activation of DAF-16 might result from inhibition of the receptor DAF-2 or to a varying extent, could be mediated by factors acting in parallel to DAF-2 (not depicted). DAF-16 activation can trigger the transcription of pro-inflammatory and metabolic genes (e.g., genes boosting aerobic glycolysis and suppressing the TCA cycle) that promote pathogen resistance. The metabolic alterations induced by DAF-16 can also lead, via yet unknown mechanisms, to chromatin remodeling that may underlie trained immunity. Therefore, the insulin cascade may be involved in both the immediate response to pathogens and in the acquisition of immune memory.