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.
Highlights
Upon priming with Candida albicans or with the fungal cell wall component -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
We performed a systematic assessment to determine whether exposure of adherent monocytes to the microbial ligands of the TLR and NOD-like receptor (NLR) classes of pattern recognition receptors, such as Pam3CSK4, LPS, flagellin, poly(I·C), R848, CpG, and Tri-DAP, influences the cell response to a secondary stimulation
In contrast to the training obtained upon engagement of dectin-1, the stimulation of the membrane receptors TLR2, Toll-like receptor 4 (TLR4), and TLR5 by inflammatory doses of Pam3CSK4 (100 g/ml), LPS (100 ng/ml), and flagellin (10 g/ml) induced a long-term tolerant state in which monocytes produced fewer proinflammatory cytokines (TNF-␣ and interleukin 6 (IL-6)) upon restimulation than did the Roswell Park Memorial Institute (RPMI)-treated control cells (Fig. 1C to E)
Summary
Upon priming with Candida albicans or with the fungal cell wall component -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. Whereas vertebrates use somatic rearrangement of immunological receptors to induce adaptive immune responses, one mechanism employed by the host defenses of invertebrates to confer adaptation to infection is alternative splicing of pattern recognition genes, such as Down syndrome cell adhesion molecule, which generates a highly diverse set of Ͼ31,000 potential alternative splice forms [10, 11]. These two molecular processes have the same consequence: they create a receptor repertoire that is sufficiently diverse for discriminating between the broad varieties of different antigens. -glucan Lipoteichoic acid (Pam3CSK4) Lipoproteins Glycosyl-phosphatidylinositols from Toxoplasma gondii Lipopolysaccharide Envelope proteins of RSV Glycosyl-phosphatidylinositols from T. gondii
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
