Training vs. Tolerance: The Yin/Yang of the Innate Immune System

Abstract

For almost nearly a century, memory functions have been attributed only to acquired immune cells. Lately, this paradigm has been challenged by an increasing number of studies revealing that innate immune cells are capable of exhibiting memory-like features resulting in increased responsiveness to subsequent challenges, a process known as trained immunity (known also as innate memory). In contrast, the refractory state of endotoxin tolerance has been defined as an immunosuppressive state of myeloid cells portrayed by a significant reduction in the inflammatory capacity. Both training as well tolerance as adaptive features are reported to be accompanied by epigenetic and metabolic alterations occurring in cells. While training conveys proper protection against secondary infections, the induction of endotoxin tolerance promotes repairing mechanisms in the cells. Consequently, the inappropriate induction of these adaptive cues may trigger maladaptive effects, promoting an increased susceptibility to secondary infections-tolerance, or contribute to the progression of the inflammatory disorder-trained immunity. This review aims at the discussion of these opposing manners of innate immune and non-immune cells, describing the molecular, metabolic and epigenetic mechanisms involved and interpreting the clinical implications in various inflammatory pathologies.

Keywords: DAMPs; PAMPs; diseases; dose; epigenetic; inflammatory; metabolic; signaling; tolerance; trained immunity.

Figure 1

Number of publications related to trained innate memory and endotoxin tolerance as adaptive manners (PubMed, January 2023).

Figure 2

Stressor-dependent induction of trained immunity. Innate immune cells as well as non-immune cells primed by specific exogenous (i.e., PAMPs) and endogenous (i.e., DAMPs) signals evoke long-term non-specific functional modifications mediated by epigenetic and metabolic rewiring toward a secondary insult. Trained cells express a multi-level entity of features characterized by the increased production of inflammatory mediators and altered epigenetic and metabolic marks, and reflected functionally by changes occurring in several cellular activities.

Figure 3

Dose-dependent induction of opposing adaptive inflammatory cues in innate immune system and non-immune cells. Innate immune cells primed by low/single dose PAMPs/DAMPs trigger a trained phenotype after subsequent encounter to a heterologous challenge, whereas high/repeated doses of PAMPs/DAMPs result in an immunotolerant phenotype. Both memory-like manners are mediated by epigenetic modifications with resulting effects on metabolism, altering various functional properties of the cells. This figure serves only for illustrative explanation of the hypothesis, since there are still missing data for such dose–response behaviors for certain types of cells.

Figure 4

A timeline of the increasing number of publications related to the induction of trained immunity and endotoxin tolerance in various inflammatory disorders. Both adaptive inflammatory processes appear to exhibit a crucial role on the suppression or progression of several inflammatory diseases (PubMed, January 2023).