Mannosyl-recognizing receptors induce an M1-like phenotype in macrophages of susceptible mice but an M2-like phenotype in mice resistant to a fungal infection

• Published in: PloS one 2013-01, Vol.8 (1), p.e54845
• Main Authors: Feriotti, Claudia, Loures, Flávio V, Frank de Araújo, Eliseu, da Costa, Tania Alves, Calich, Vera L G
• Format: Article
• Language: English
• Subjects: Animals; Antifungal Agents - pharmacology; Antigens; Arginase; Arginase - metabolism; Biology; Bone morphogenetic proteins; Candida albicans; Cell activation; Chitinase; Complement receptor 3; Cytokines; Cytokines - biosynthesis; Cytotoxicity, Immunologic; Differentiation; Disease Susceptibility; Drug Synergism; Fungal infections; Fungi; Fungicides; Gene expression; Genetic aspects; Glucan; Health aspects; Immune system; Immunity; Immunological tolerance; Inflammation; Innate immunity; Interferon-gamma - pharmacology; Interleukin 12; Interleukin 6; Lectins; Lectins, C-Type - antagonists & inhibitors; Lectins, C-Type - metabolism; Lymphocytes; Macrophage-1 Antigen - metabolism; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mannan; Mannans - pharmacology; Mannose; Mannose Receptor; Mannose-Binding Lectins - antagonists & inhibitors; Mannose-Binding Lectins - metabolism; Medicine; Membranes; Mice; Microorganisms; Monoclonal antibodies; Mycoses; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide Synthase Type II - metabolism; Paracoccidioides - immunology; Paracoccidioides brasiliensis; Paracoccidioidomycosis - immunology; Paracoccidioidomycosis - metabolism; Pathogens; Phagocytes; Phagocytosis - drug effects; Phagocytosis - immunology; Phenotype; Proteins; Receptors; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - metabolism; Receptors, Pattern Recognition - metabolism; Recognition; Signaling; SOCS-1 protein; South American blastomycosis; TLR2 protein; TLR4 protein; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - antagonists & inhibitors; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Transforming growth factors; Tumor necrosis factor-α; Yeasts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0054845

In addition to alpha1,3 glucan, mannan and mannan-linked proteins are expressed in the outer layer of Paracoccidioides brasiliensis yeasts. The recognition of mannosyl residues by multiple pathogen recognition receptors, such as the mannose receptor (MR), complement receptor 3 (CR3) and toll-like receptor 4 (TLR4) on macrophage membranes can influence macrophage activation and the mechanisms of innate immunity against fungal pathogens. The aim of this study was to clarify the role of these receptors in the interaction between P. brasiliensis and macrophages from resistant (A/J) and susceptible (B10.A) mice. Therefore, the phagocytic, fungicidal and secretory abilities of macrophages were evaluated in the presence of mannan and antibodies against MR, CR3 and TLR4. We verified that mannan increased and anti-MR antibody decreased the killing ability and nitric oxide production of macrophages. The specific blockade of MR, CR3 and TLR4 by monoclonal antibodies impaired fungal recognition and modulated the production of cytokines. Mannan or P. brasiliensis induced decreased expression of MR and TLR2 on A/J macrophages, whereas CR3, TLR4 and TLR2 were reduced on B10.A cells. Importantly, both mannan and P. brasiliensis induced the production of IL-12 by B10.A macrophages, whereas TGF-β, TNF-α and IL-6 were produced by A/J cells. In addition, B10.A macrophages exhibited a prevalent expression of inducible NO-synthase and SOCS3 (suppressor of cytokine signaling-3), indicating a pro-inflammatory, "M1-like" differentiation. In contrast, the elevated expression of arginase-1, found in inflammatory zone-1 (FIZZ1), YM1 (CHI313, chitinase-like lectin), and SOCS1, typical markers of alternatively activated macrophages, indicates a prevalent "M2-like" differentiation of A/J macrophages. In conclusion, our data reveal that several mannosyl-recognizing receptors coordinate the apparently paradoxical innate response to paracoccidioidomycosis, in which resistance is initially mediated by alternatively activated phagocytes and tolerance to fungal growth, whereas susceptibility is linked to classically activated macrophages and the efficient control of fungal growth.