Dectin-1 ligands produce distinct training phenotypes in human monocytes through differential activation of signaling networks

Abstract Cells of the innate immune system retain memory of prior exposures through a process known as innate immune training. β-glucan, a Dectin-1 ligand purified from the Candida albicans cell wall, has been one of the most widely utilized ligands for inducing innate immune training. However, many...
Ausführliche Beschreibung

Abstract Cells of the innate immune system retain memory of prior exposures through a process known as innate immune training. β-glucan, a Dectin-1 ligand purified from the Candida albicans cell wall, has been one of the most widely utilized ligands for inducing innate immune training. However, many Dectin-1 ligands exist, and it is not known whether these all produce the same phenotype. Using a well-established in vitro model of innate immune training, we compared two commercially available Dectin-1 agonists, zymosan and depleted zymosan, with the gold standard β-glucan in the literature. We found that depleted zymosan, a β-glucan purified from Saccharomyces cerevisiae cell wall through alkali treatment, produced near identical effects as C. albicans β-glucan. However, untreated zymosan produced a distinct training effect from β-glucans at both the transcript and cytokine level. Training with zymosan diminished, rather than potentiated, induction of cytokines such as TNF and IL-6. Zymosan activated NFκB and AP-1 transcription factors more strongly than β-glucans. The addition of the toll-like receptor (TLR) ligand Pam3CSK4 was sufficient to convert the training effect of β-glucans to a phenotype resembling zymosan. We conclude that differential activation of TLR signaling pathways determines the phenotype of innate immune training induced by Dectin-1 ligands. Ausführliche Beschreibung