Collaborative Induction of Inflammatory Responses by Dectin-1 and Toll-like Receptor 2

Abstract

Toll-like receptors (TLRs) mediate recognition of a wide range of microbial products including lipopolysaccharides, lipoproteins, flagellin, and bacterial DNA, and signaling through TLRs leads to the production of inflammatory mediators. In addition to TLRs, many other surface receptors have been proposed to participate in innate immunity and microbial recognition, and signaling through some of these receptors is likely to cooperate with TLR signaling in defining inflammatory responses. In this report we have examined how dectin-1, a lectin family receptor for β-glucans, collaborates with TLRs in recognizing microbes. Dectin-1, which is expressed at low levels on macrophages and high levels on dendritic cells, contains an immunoreceptor tyrosine-based activation motif–like signaling motif that is tyrosine phosphorylated upon activation. The receptor is recruited to phagosomes containing zymosan particles but not to phagosomes containing immunoglobulin G–opsonized particles. Dectin-1 expression enhances TLR-mediated activation of nuclear factor κB by β-glucan–containing particles, and in macrophages and dendritic cells dectin-1 and TLRs are synergistic in mediating production of cytokines such as interleukin 12 and tumor necrosis factor α. Additionally, dectin-1 triggers production of reactive oxygen species, an inflammatory response that is primed by TLR activation. The data demonstrate that collaborative recognition of distinct microbial components by different classes of innate immune receptors is crucial in orchestrating inflammatory responses.

NADPH oxidase of human dendritic cells: Role in Candida albicans killing and regulation by interferons, dectin‐1 and CD206

“…These results agree with the reports that in murine macrophages dectin-1 plays a role in ROS production [27,39], and with previous findings demonstrating an inhibitory effect of CD206 on proinflammatory cytokine release [40,44,47]. Moreover, these results may explain why Candida does not elicit the NADPH oxidase activity in DC.…”

“…4C), confirming early studies [39,42]. Consistently with reports showing that dectin-1 induces ROS production in murine macrophages [27,39], this finding suggests that dectin-1 could mediate NADPH oxidase activation in human DC. …”

“…It is known that DC interact with yeasts essentially by the mannose-binding receptors CD206 [22,31] and DCspecific intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN) [32,33], the b-glucan receptor dectin-1 [27,32,[34][35][36][37], and TLR2 [32,38,39]. Therefore, we analyzed Candida uptake in the presence of mannan, which binds both CD206 and DC-SIGN [40,41] and interferes with particle internalization by these receptors [42], or laminarin, a specific dectin-1 inhibitor [27,35,40,41,43].…”

Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia

“…In the case of gram-positive bacterial components, evidence suggests that CD14 can enhance TLR2-dependent signaling in macrophages (Harokopakis and Hajishengallis, 2005;Manukyan et al, 2005;Schroder et al, 2003). The majority of Toll-like receptors identified to date utilize a common signal transduction pathway with minor differences that appear to confer specificity in response to distinct ligands (Akira and Hemmi, 2003;Gantner et al, 2003;Takeda et al, 2003). MyD88 is a central player in the signal transduction pathways of the IL-1R, IL-18R, and TLRs (with the exception of TLR3), providing a bridge between the cytoplasmic domains of these receptors and IL-1R-associated kinase (IRAK) (Akira and Hemmi, 2003;Kawai and Akira, 2005;Takeda et al, 2003;Yamamoto et al, 2004).…”

TLR2‐activated human langerhans cells promote Th17 polarization via IL‐1β, TGF‐β and IL‐23

“…It was reported that TLR2 together with Dectin-1 is capable of sensing zymosan in murine bone marrow-derived DC and that hyphae of Candida albicans prime monocyte-mediated Th17 responses [24,25]. In case of injury and breakdown of the skin barrier or otherwise microbial invasion, LC gain access to TLR-agonist-bearing pathogens.…”