Internalization of Dectin-1 terminates induction of inflammatory responses.
Dectin-1 is a pattern-recognition receptor recognizing beta-(1,3)-glucans found on fungal cell walls. Dectin-1 plays an important role in immunity to fungi by mediating phagocytic clearance of fungal particles and inducing transcription of innate response genes. We show here that the two processes are linked and that Dectin-1 signalling for inflammation is attenuated by phagocytosis. Blocking Dectin-1 ligand-dependent internalization using either actin polymerization or dynamin inhibitors, large non-phagocytosable beta-glucan particles or poorly phagocytic cells leads in all cases to enhanced and sustained activation of downstream signalling pathways and culminates in production of high levels of pro-inflammatory cytokines. These findings establish the importance of phagocytosis not only in the clearance of pathogens, but also in the modulation of pattern-recognition receptor signalling and strongly suggest that internalization is the first step to attenuation of Dectin-1-mediated pro-inflammatory responses.
Hernanz-Falcón
Patricia
P
Immunobiology Laboratory, Cancer Research UK, London Research Institute, London, UK.
Joffre
Olivier
O
Williams
David L
DL
Reis e Sousa
Caetano
C
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology; D000818:Animals; D016207:Cytokines / Q000276:immunology*; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology*; D037181:Lectins, C-Type; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology* / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology*; D015398:Signal Transduction; D047071:beta-Glucans / Q000276:immunology; D000099181:Dectin-1
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D037181:Lectins, C-Type; D008565:Membrane Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D053594:Myeloid Differentiation Factor 88; D009419:Nerve Tissue Proteins; D047071:beta-Glucans; D000099181:Dectin-1; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse