Recognition of the fungal cell wall component beta-glucan by the host receptor Dectin-1 display broad immunomodulatory properties. As such, stimulation of phagocytosis and activation of the oxidative burst are essential to engulf and kill the pathogens. Phagocytic cells, such as monocytes, are also key mediators of the early host inflammatory responses to infections. Whether an interplay exists between phagocytosis and the inflammatory response of human monocytes to fungal beta-glucan remains to be characterized. Here we show that intact phagocytosis of heat-killed Candida albicans is essential to trigger inflammation and cytokine release. In contrast, inhibition of actin-dependent phagocytosis of particulate (1,3/1,6)-beta-glucan induces a strong inflammatory signature. Activation of human monocytes results classical caspase-1 inflammasome formation, generation of strong oxidative burst, NF-kB activation, as well as increased release of inflammatory cytokines. The sustained monocyte activation induced by the fungal beta-glucan particles upon actin cytoskeleton disruption relies on Dectin-1 and can be finely regulated by specific inhibitors of the downstream signaling pathway. Our results highlight the mechanism by which phagocytosis tightly controls the activation of phagocytes by microbial pathogens and strongly suggest that actin cytoskeleton dynamic is an essential determinant of the host’s susceptibility or resistance to invasive fungal infections.

6 / Impaired phagocytosis directs human monocyte activation in response to fungal derived ß-glucan particles