Abstract
Dectin-1 is a pattern recognition receptor (PRR) that recognizes β-glucans and plays a major role in the immunity against fungal pathogens. Paracoccidioides brasiliensis, the causative agent of paracoccidioidomycosis, has a sugar-rich cell wall mainly composed of mannans and glucans. To investigate the role of dectin-1 in the innate immunity of resistant (A/J) and susceptible (B10.A) mice to P. brasiliensis infection, we evaluated the role of curdlan (a dectin-1 agonist) and laminarin (a dectin-1 antagonist) in the activation of macrophages from both mouse strains. We verified that curdlan has a negligible role in the activation of B10.A macrophages but enhances the phagocytic and fungicidal abilities of A/J macrophages. Curdlan up-regulated the expression of costimulatory molecules and PRRs in A/J macrophages that express elevated levels of dectin-1, but not in B10.A cells. In addition, curdlan treatment inhibited arginase-1 and enhanced NO-synthase mRNA expression in infected A/J macrophages but had not effect in B10.A cells. In contrast, laminarin reinforced the respective M2/M1 profiles of infected A/J and B10.A macrophages. Following curdlan treatment, A/J macrophages showed significantly higher Syk kinase phosphorylation and expression of intracellular pro-IL-1β than B10.A cells. These findings led us to investigate if the NRLP3 inflammasome was differently activated in A/J and B10.A cells. Indeed, compared with B10.A cells A/J macrophages showed an increased expression of NALP3, ASC, and IL-1β mRNA. They also showed elevated caspase-1 activity and secreted high levels of mature IL-β and IL-18 after curdlan treatment and P. brasiliensis infection. Our data demonstrate that soluble and particulate β-glucans exert opposed modulatory activities on macrophages of diverse genetic patterns. Moreover, the synergistic action of dectin-1 and NALP3 inflammasome were for the first time associated with the innate response of resistant hosts to P. brasiliensis infection.
Highlights
Dectin-1 is an innate immune pattern recognition receptor (PRR) that recognizes β-glucans in the cell walls of fungi, and is a crucial receptor for protective immunity against fungal pathogens
A/J macrophages that express high levels of dectin-1 showed an enhanced Syk kinase phosphorylation and NALP3 inflammasome activation resulting in increased levels of caspase-1 activity and increased secretion of IL-1β and IL-18. These findings demonstrate that macrophages from resistant mice display a prevalent dectin-1 signaling and NLRP3 inflammasome activation when infected by P. brasiliensis yeasts
Curdlan and Laminarin have Contrasting Effects on the Activation of A/J and B10.A Macrophages upon P. brasiliensis Infection First, we determined the effect of curdlan on the phagocytic ability of A/J and B10.A macrophages co-cultivated with P. brasiliensis (Figures 1A,B)
Summary
Dectin-1 is an innate immune pattern recognition receptor (PRR) that recognizes β-glucans in the cell walls of fungi, and is a crucial receptor for protective immunity against fungal pathogens. Interaction of microbial β-glucans with dectin-1 expressed on myeloid phagocytes [macrophages, dendritic cells (DCs), and neutrophils] activates phagocytosis, reactive oxygen species (ROS) production, synthesis of inflammatory cytokines and chemokines and influences the development of adaptive immunity (Goodridge et al, 2009; Brown, 2011). Dectin ligation by β-glucan-containing particles triggers Src/Sykdependent downstream signals in myeloid cells to activate MAP kinases, as well as NF-κB and NFAT transcription factors (Goodridge et al, 2007, 2011). The secretion of IL-1β by β-glucan-activated macrophages was shown to require two steps, a dectin-1/Syk-kinase dependent production of pro-IL1β and the subsequent activation of NLRP3 (nucleotide-binding oligomerization domain-like receptor P3) inflammasome that employs the adaptor associated speck-like protein (ASC) and caspase-1 to cleave pro-IL-1β into its mature bioactive form (Kankkunen et al, 2010)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
