Dectin-1 Controls TLR9 Trafficking to Phagosomes Containing β-1,3 Glucan

Abstract

Dectin-1 and TLR9 play distinct roles in the recognition and induction of innate immune responses to Aspergillus fumigatus and Candida albicans. Dectin-1 is a receptor for the major fungal cell wall carbohydrate β-1,3 glucan that induces inflammatory cytokines and controls phagosomal maturation through Syk activation. TLR9 is an endosomal Toll-like receptor that also modulates the inflammatory cytokine response to fungal pathogens. In this study, we demonstrate that β-1,3 glucan beads are sufficient to induce dynamic redistribution and accumulation of cleaved TLR9 to phagosomes. Trafficking of TLR9 to A. fumigatus and C. albicans phagosomes requires Dectin-1 recognition. Inhibition of phagosomal acidification blocks TLR9 accumulation on phagosomes containing β-1,3 glucan beads. Dectin-1 mediated Syk activation is required for TLR9 trafficking to β-1,3 glucan, A. fumigatus, and C. albicans containing phagosomes. In addition, Dectin-1 regulates TLR9 dependent gene expression. Collectively, our study demonstrates that recognition of β-1,3 glucan by Dectin-1 triggers TLR9 trafficking to β-1,3 glucan-containing phagosomes, which may be critical in coordinating innate anti-fungal defense.

Genetic susceptibility to severe asthma with fungal sensitization

“…TLR9 is an endosomal TLR that modulates the inflammatory cytokine response to A. fumigatus (Bellocchio et al., ; Carvalho et al., ; Khan et al., ; Ramaprakash, Ito, Standiford, Kunkel, & Hogaboam, ). Phagosomal TLR9 expression is controlled by dectin‐1 (Khan et al., ) and is increased in neutrophils challenged with conidia and hyphae, and induction of TLR9 expression positively correlates with the induction of antifungal effector functions by these cells (Bellocchio et al., ). In a mouse model of fungal asthma, TLR9 −/− mice exhibited significantly lower airway hyper‐responsiveness after challenge with resting conidia compared to the TLR9 +/+ mice and A. fumigatus ‐sensitized TLR9 −/− mice exhibited pulmonary fungal growth up to 28 days after challenge with swollen conidia, an observation that was not found in A. fumigatus ‐sensitized TLR9 +/+ mice (Ramaprakash et al., ).…”

“…In allergic models of A. fumigatus exposure, dectin‐1 activation can lead to the induction of CCL17 (Lilly et al., ), and CCL17 affects CCL2 levels (Carpenter & Hogaboam, ). Dectin‐1 also controls trafficking of TL9 to A. fumigatus containing phagosomes (Khan et al., ), and TLR9 as well as TLR3 are involved in the production of IL‐10 (Carvalho et al., ; de Luca et al., ; Ramaprakash & Hogaboam, ). Previous studies have shown how SNPs in different genes such as dectin‐1 and CCL2 can have synergistic effects on susceptibility to aspergillosis (Sainz et al., ), and it may be that further analysis will prove that this is the case with SAFS.…”

LC3-associated phagocytosis: a crucial mechanism for antifungal host defence againstAspergillus fumigatus

“…The recruitment of TLR9 is, in contrast to LC3 (Kyrmizi et al ., ), shown to be independent of the germination stage of conidia (Kasperkovitz et al ., ). Although more recent studies show that TLR9 recruitment to Aspergillus ‐containing phagosomes is dependent on Dectin‐1, phagocytosis of β‐glucan beads was already sufficient to traffic TLR9 to the phagosome (Khan et al ., ). In contrast to LAP, which requires the absence of both rodlet proteins ( ΔrodA ) and melanin ( Δalb1 ) (Akoumianaki et al ., ), localization of TLR9 to the phagosome does not require this removal (Kasperkovitz et al ., ).…”

Endolysosomal compartments as platforms for orchestrating innate immune and metabolic sensors

“…A portion of TLR4/MD‐2 is colocalized with Rab11a in the endocytic recycling compartment and recruited to phagosomes in a manner dependent on Rab11a . TLR3, TLR7, TLR8, and TLR9 are recruited to phagosomes containing fungi or bacteria . Recruitment of endosomal TLRs to phagosomes seems to depend on activation of the tyrosine kinase Syk.…”