The β-Glucan Receptor Dectin-1 Activates the Integrin Mac-1 in Neutrophils via Vav Protein Signaling to Promote Candida albicans Clearance

Abstract

SUMMARY Resistance to fungal infections is attributed to engagement of host pattern-recognition receptors, notably the β-glucan receptor Dectin-1 and the integrin Mac-1, which induce phagocytosis and antifungal immunity. However, the mechanisms by which these receptors coordinate fungal clearance are unknown. We show that upon ligand binding, Dectin-1 activates Mac-1 to also recognize fungal components and this stepwise process is critical for neutrophil cytotoxic responses. Both Mac-1 activation and Dectin-1- and Mac-1-induced neutrophil effector functions require Vav1 and Vav3, exchange factors for RhoGTPases. Mac-1- or Vav1,3-deficient mice have increased susceptibility to systemic candidiasis that is not due to impaired neutrophil recruitment but defective intracellular killing of C. albicans yeast forms, and Mac-1 or Vav1,3 reconstitution in hematopoietic cells restores resistance. Our results demonstrate that antifungal immunity depends on Dectin-1-induced activation of Mac-1 functions that is coordinated by Vav proteins, a pathway that may localize cytotoxic responses of circulating neutrophils to infected tissues.

IL-33 Priming Regulates Multiple Steps of the Neutrophil-Mediated Anti-Candida albicans Response by Modulating TLR and Dectin-1 Signals

“…Recent studies have shown that dectin-1 signaling is critical for the activation of CR3 to promote the phagocytic activity of neutrophils and C. albicans clearance (39). The previous results shown in Fig.…”

“…TLRs and dectin-1 were previously reported to be necessary for protection from C. albicans infection (15)(16)(17)(18)(39)(40)(41). Collaborative recognition of distinct microbial components by TLRs and dectin-1 synergistically induced the production of proinflammatory cytokines (42,43).…”

IL-33 Enhances Host Tolerance to Candida albicans Kidney Infections through Induction of IL-13 Production by CD4+ T Cells

“…In fact, IL-33 was shown to enforce TLR and Dectin-1 signaling to upregulate complement receptor 3 (CR3) in neutrophils and increase their phagocytic activity (13,14), as well as to increase the Dectin-1-induced activation of Mac-1, a component of CR3 (20). IL-33-induced CR3 activation also results in the production of high levels of reactive oxygen species and fungicidal activity in neutrophils.…”

Immunity against fungi

“…These data can be reconciled if the major role of dectin-1/CARD9 is to modulate NADPH oxidase and fungal killing via soluble mediators, rather than by cell-intrinsic activation. β2 integrins and TLR signaling can collaborate with dectin-1 to mount macrophage inflammatory responses to H. capsulatum and other fungi (44,45).…”