Trained immunity — basic concepts and contributions to immunopathology

Abstract

Trained immunity is a functional state of the innate immune response and is characterized by long-term epigenetic reprogramming of innate immune cells. This concept originated in the field of infectious diseases — training of innate immune cells, such as monocytes, macrophages and/or natural killer cells, by infection or vaccination enhances immune responses against microbial pathogens after restimulation. Although initially reported in circulating monocytes and tissue macrophages (termed peripheral trained immunity), subsequent findings indicate that immune progenitor cells in the bone marrow can also be trained (that is, central trained immunity), which explains the long-term innate immunity-mediated protective effects of vaccination against heterologous infections. Although trained immunity is beneficial against infections, its inappropriate induction by endogenous stimuli can also lead to aberrant inflammation. For example, in systemic lupus erythematosus and systemic sclerosis, trained immunity might contribute to inflammatory activity, which promotes disease progression. In organ transplantation, trained immunity has been associated with acute rejection and suppression of trained immunity prolonged allograft survival. This novel concept provides a better understanding of the involvement of the innate immune response in different pathological conditions, and provides a new framework for the development of therapies and treatment strategies that target epigenetic and metabolic pathways of the innate immune system.

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

“…Trained immunity represents a functional state of the innate immune cells and tissue-resident stem cells adjusting their response to subsequent insults, characterized particularly by a prolonged activation after a resting period, orchestrated mainly by epigenetic reprogramming and the metabolic rewiring of cells [ 24 ]. It describes a property of innate immune system to mount memory-like responses against past microbial and non-microbial challenges [ 20 , 21 , 24 ].…”

“…Trained immunity represents a functional state of the innate immune cells and tissue-resident stem cells adjusting their response to subsequent insults, characterized particularly by a prolonged activation after a resting period, orchestrated mainly by epigenetic reprogramming and the metabolic rewiring of cells [ 24 ]. It describes a property of innate immune system to mount memory-like responses against past microbial and non-microbial challenges [ 20 , 21 , 24 ]. To date, studies have shown that trained immunity can be maintained in innate immune cells for months up to decades, a process occurring in the bone marrow progenitor cells–central trained immunity, or for days up to a week in circulating innate immune cells–peripheral training [ 21 , 49 , 50 , 51 , 52 ].…”

“…In addition to the aforementioned PAMPs, DAMPs, such as oxLDL, heme, urate, vimentin and high-mobility group box 1 (HMGB1), recognized mainly by TLR4, can be targeted for trained immunity modulation [ 24 , 117 , 118 ]. Pre-exposure to specific DAMPs as non-microbial triggers can induce the functional reprogramming of innate immune cells triggering an altered immune response toward a subsequent challenge [ 117 ].…”

“…Pre-exposure to specific DAMPs as non-microbial triggers can induce the functional reprogramming of innate immune cells triggering an altered immune response toward a subsequent challenge [ 117 ]. DAMPs released during tissue injury from cell death or after organ transplantation allow innate immune cells to elicit long-term epigenetic changes at the promoters of inflammatory genes and cause metabolic rewiring [ 24 , 119 ]. Vimentin and HMGB1 represent inflammatory mediators upregulated during organ transplantation, responsible for acute and chronic transplant rejection [ 120 , 121 ].…”

“…Trained immunity, known also as innate memory or trained innate memory (abbr. TRIM), describes a long-term functional reprogramming evoked by various endogenous danger signals (damage-associated molecular patterns, DAMPs) released upon cellular stress or tissue injury, or exogenous pathogenic conserved molecules (pathogen-associated molecular patterns, PAMPs) [ 21 , 22 , 23 , 24 ]. Notably, recent studies have demonstrated also the capability of hormones to support the induction of trained immunity, especially by sex-related (i.e., β-estradiol) hormones or aldosterone as a mineralocorticoid that regulates electrolyte homeostasis and affects many cardiovascular inflammatory events [ 25 , 26 ].…”