Balancing tissue homeostasis and inflammatory responses against Candida albicans infections: is it a matter of mast cells' immunological memory?

Mast cells (MC) are long lived immune cells widely distributed at mucosal surfaces among the first immune cell type that can get in contact with the external environment. This study aims to unravel the mechanisms of reciprocal influence between mucosal mast cells, the human commensal Candida albicans and microbial bioproducts. Stimulation of bone marrow-derived mast cells (BMMC) with live forms of C. albicans induced the release of TNF-α, IL-6, IL-13 and IL-4. Quite interestingly, BMMC were able to engulf C. albicans hyphae, rearranging their α-tubulin cytoskeleton accumulating LAMP1+ vesicles at the phagocytic synapse with the fungus. Infected MCs failed to promote macrophage chemotaxis but instead increased their crawling ability. On the other side, resting MCs inhibited macrophage phagocytosis of C. albicans in a contact-dependent manner. Several microbial ligands are known to induce immune memory on macrophages and natural killer cells. To determine whether this is true also for MCs and if their training could afford protection against fungal infections, BMMCs were stimulated for 24 hour with microbial ligands, washed and allowed to rest for 6 days and then restimulated with LPS or C. albicans. LPS-primed cells showed a decreased release of TNF-α and IL-6 upon restimulation with LPS (a condition known as endotoxin tolerance) but an increased release of TNF-α during fungal challenge. The impaired response during endotoxin tolerance relied on the impaired activation of the PI3K-AKT-p38 pathway, which led to a decreased NF-κB activation and TNF-α expression. On the other side, the training effect of LPS was mediated by the enhanced activation of NF-κB and the sustained basal transcription of TNF-α. These results indicate that MCs are important gatekeeper of tissue homeostasis. Signals received from the microbiota can shape their immune memory, dampening the inflammation in response to bacterial LPS but affording protection during fungal infections.