Trained Immunity or Tolerance: Opposing Functional Programs Induced in Human Monocytes after Engagement of Various Pattern Recognition Receptors

Abstract

Upon priming with Candida albicans or with the fungal cell wall component β-glucan, monocytes respond with an increased cytokine production upon restimulation, a phenomenon termed “trained immunity.” In contrast, the prestimulation of monocytes with lipopolysaccharide has long been known to induce tolerance. Because the vast majority of commensal microorganisms belong to bacterial or viral phyla, we sought to systematically investigate the functional reprogramming of monocytes induced by the stimulation of pattern recognition receptors (PRRs) with various bacterial or viral ligands. Monocytes were functionally programmed for either enhanced (training) or decreased (tolerance) cytokine production, depending on the type and concentration of ligand they encountered. The functional reprogramming of monocytes was also associated with cell shape, granulocity, and cell surface marker modifications. The training effect required p38- and Jun N-terminal protein kinase (JNK)-mediated mitogen-activated protein kinase (MAPK) signaling, with specific signaling patterns directing the functional fate of the cell. The long-term effects on the function of monocytes were mediated by epigenetic events, with both histone methylation and acetylation inhibitors blocking the training effects. In conclusion, our experiments identify the ability of monocytes to acquire adaptive characteristics after prior activation with a wide variety of ligands. Trained immunity and tolerance are two distinct and opposing functional programs induced by the specific microbial ligands engaging the monocytes.

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye

“…Similar protection has been observed in ischemia or endotoxin tolerance, in which preexposure to ischemia or lipopolysaccharide results in attenuated tissue injury during subsequent insults (23)(24)(25). The nature of the induced protection and underlying mechanisms of preconditioning are not yet clear, but studies suggest that innate immune cells such as monocytes/ macrophages play a central role (26)(27)(28). Here we found that the MSC preconditioning involved a distinct subset of suppressive MHC II + B220 + CD11b + monocytes/macrophages in the lung.…”

“…Recent studies showed that monocytes/macrophages can reprogram their responses toward immunogenic or tolerogenic phenotypes depending on the type and concentration of ligands they encountered, in the phenomenon termed "trained immunity and tolerance" (27,28). In this context, our study provides a possibility that MSCs use the plasticity of monocytes/macrophages and prime them to produce tolerance.…”

The fifth dimension of innate immunity

“…Strikingly, corresponding reactions could be also observed under in vivo conditions. Pretreatment of immunodeficient mice missing T-cells and Bcells (SCID) with BCG vaccine or β-glucan induced a significantly enhanced and sustained immune response (Ifrim et al 2014;Quintin et al 2014). The authors define the adaptive response of innate immune cells as "Trained immunity" and show strict dependence of the reprogramming of innate immune cells on the specific pathogen applied.…”

Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders

“…For example, moderate to high doses of a variety of PAMP and PRR ligands, such as LPS (100 μg ml − 1 ), Pam3CSK4 (100 μg ml − 1 ), flagellin (10 μg ml − 1 ) and Poly(I:C) (100 μg ml − 1 ) (which all engage TLRs) induced heterogeneous tolerance in human monocytes. 34 Lower doses (0.1 pg ml − 1 to 1 μg ml − 1 ) however, induced heterogeneous training. In contrast, low to moderate doses of β-glucan (1 μg ml − 1 ), Tri-DAP (10 μg ml − 1 ) and muramyl dipeptide (10 μg ml − 1 ) (which engage NODs), all induced training (up to fivefold increases in TNF-α).…”

“…For example, whilst high-dose LPS results in decreased production of proinflammatory molecules upon re-exposure to LPS, low-dose LPS exposure results in increase production of proinflammatory molecules upon re-exposure to LPS. 34 That this memory effect is heterogeneous and long lasting has important implications, as it may set the stage for a proinflammatory responsive state in response to a diverse array of temporally distant immunostimulatory events. Table 1 lists some of the main features of trained innate immunity, as well as potential consequences for neuropsychiatric disorders.…”