Nucleosides from Phlebotomus papatasi salivary gland ameliorate murine collagen-induced arthritis by impairing dendritic cell functions

• Published in: The Journal of immunology (1950) 2011-10, Vol.187 (8), p.4347-4359
• Main Authors: Carregaro, Vanessa, Sá-Nunes, Anderson, Cunha, Thiago M, Grespan, Renata, Oliveira, Carlo J F, Lima-Junior, Djalma S, Costa, Diego L, Verri, Jr, Waldiceu A, Milanezi, Cristiane M, Pham, Van My, Brand, David D, Valenzuela, Jesus G, Silva, João S, Ribeiro, José M C, Cunha, Fernando Q
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Cell Proliferation - drug effects; Chromatography, High Pressure Liquid; Dendritic Cells - drug effects; Dendritic Cells - immunology; Female; Male; Mice; Mice, Inbred DBA; Nucleosides - pharmacology; Phlebotomus - chemistry; Phlebotomus papatasi; Reverse Transcriptase Polymerase Chain Reaction; Salivary Glands - chemistry; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tissue Extracts - chemistry; Tissue Extracts - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1003404

Among several pharmacological compounds, Phlebotomine saliva contains substances with anti-inflammatory properties. In this article, we demonstrated the therapeutic activity of salivary gland extract (SGE) of Phlebotomus papatasi in an experimental model of arthritis (collagen-induced arthritis [CIA]) and identified the constituents responsible for such activity. Daily administration of SGE, initiated at disease onset, attenuated the severity of CIA, reducing the joint lesion and proinflammatory cytokine release. In vitro incubation of dendritic cells (DCs) with SGE limited specific CD4(+) Th17 cell response. We identified adenosine (ADO) and 5'AMP as the major salivary molecules responsible for anti-inflammatory activities. Pharmacologic inhibition of ADO A2(A) receptor or enzymatic catabolism of salivary nucleosides reversed the SGE-induced immunosuppressive effect. Importantly, CD73 (ecto-5'-nucleotidase enzyme) is expressed on DC surface during stage of activation, suggesting that ADO is also generated by 5'AMP metabolism. Moreover, both nucleosides mimicked SGE-induced anti-inflammatory activity upon DC function in vitro and attenuated establishment of CIA in vivo. We reveal that ADO and 5'AMP are present in pharmacological amounts in P. papatasi saliva and act preferentially on DC function, consequently reducing Th17 subset activation and suppressing the autoimmune response. Thus, it is plausible that these constituents might be promising therapeutic molecules to target immune inflammatory diseases.