CD14 is critical for TLR2-mediated M1 macrophage activation triggered by N-glycan recognition

Author(s)

da Silva, Thiago Aparecido ; Zorzetto-Fernandes, Andre L. V. ; Cecilio, Nerry T. ; Sardinha-Silva, Aline ; Fernandes, Fabricio Freitas ; Roque-Barreira, Maria Cristina

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 7, AUG 1 2017.
• Web of Science Citations: 12

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-kappa B 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. (AU)

• FAPESP's process: 16/10446-4 - Mechanisms of immunomodulation by ArtinM: basis for the development of new anti-fungal therapy
• Grantee: Maria Cristina Roque Antunes Barreira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/04877-2 - Design of new therapeutic strategies, based on the carbohydrate recognition, against cryptococcosis
• Grantee: Thiago Aparecido da Silva
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/04088-0 - Lectin from pathogens
• Grantee: Maria Cristina Roque Antunes Barreira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/09611-0 - Effect of lectin ArtinM on murine CD4+ T and CD8+ T cells
• Grantee: Thiago Aparecido da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 10/02122-8 - Evaluation of imunomodulator ArtinM, a TLR2 ligand, on the resolution of the infection by different species of Leishmania
• Grantee: André Luiz Vieira Zorzetto Fernandes
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 09/16146-9 - Induced cell activation by ArtinM: interference of the quaternary structure of different recombinant forms on neutrophil functions and interaction with glycosylated receptors on surface of these cells.
• Grantee: Nerry Tatiana Cecilio
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 12/12950-0 - Study on signaling pathways triggered by interaction of microneme proteins of Toxoplasma gondii with glycans toll-like receptors 2 and 4
• Grantee: Aline Sardinha da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate