Abstract
Agonist interaction with Toll-like receptors (TLRs) induces T cell-mediated immunity, which is effective against intracellular pathogens. Consequently, TLR agonists are being tried as immunomodulatory agents. The lectin ArtinM targets TLR2 N-glycans on macrophages, induces cytokines production, and promotes T helper-1 immunity, a process that culminates in resistance to several parasitic and fungal infections in vivo. Because co-receptors influence agonist binding to TLRs, we investigated whether CD14 is required for macrophage activation induced by ArtinM. Macrophages from wild-type mice stimulated by ArtinM not only produced cytokines but also had the following activation profile: (i) expression of M1 polarization markers; (ii) nitrite oxide production; (iii) cellular migration; (iv) enhanced phagocytic and fungicide activity; (v) modulation of TLR2 expression; and (vi) activation of NF-κB pathway. This activation profile induced by ArtinM was evaluated in macrophages lacking CD14 that showed none of the ArtinM effects. We demonstrated by immunoprecipitation and sugar inhibition assays the physical interaction of ArtinM, TLR2, and CD14, which depends on recognition of the trimannoside that constitutes the core of N-glycans. Thus, our study showed that CD14 is critical for ArtinM-induced macrophage activation, providing fundamental insight into the design of anti-infective therapies based on carbohydrate recognition.
Highlights
The antibodies produced after vaccination neutralize the inoculums of extracellular pathogens and prevent infections[1]
Plant lectins are represented by ArtinM, which interacts with TLR2 N-glycans to induce cell activation and pro-inflammatory cytokine production, culminating in the development of Th1 immunity
Macrophage activation induced by ArtinM was originally related to the interaction of the lectin with TLR2, which was found to occur in a carbohydrate recognition-dependent manner[31]; this recognition is responsible for the immunomodulatory activity of ArtinM that accounts for the protection conferred on P. brasiliensis-infected mice[27, 28]
Summary
The antibodies produced after vaccination neutralize the inoculums of extracellular pathogens and prevent infections[1]. We previously reported that ArtinM, a D-mannose-binding lectin[24], confers protection against intracellular parasites and fungal infections[25,26,27,28,29,30] This activity was attributed to ArtinM interaction with TLR2 N-glycans[31], which is followed by IL-12 production and establishment of Th1 immunity. The ArtinM effects were shown to depend on carbohydrate recognition because direct binding to TLR2 was inhibited by the trimannoside targeted by ArtinM32, 33, which constitutes the core of N-glycans These data demonstrated that a carbohydrate recognition protein might function as a TLR agonist and exert immunomodulatory activity. Elucidating the details of ArtinM interaction with CD14 allows a better understanding of the structural basis of immunomodulation induced by carbohydrate recognition and provides fundamental insights for the design of lectin-mimetic drugs[37] for anti-infective therapies
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