Leishmania expressed lipophosphoglycan interacts with Toll-like receptor (TLR)-2 to decrease TLR-9 expression and reduce anti-leishmanial responses.

Abstract

Two different Toll-like receptors (TLRs) have been shown to play a role in host responses to Leishmania infection. TLR-2 is involved in parasite survival in macrophages upon activation by lipophosphoglycan (LPG), a virulence factor expressed by Leishmania. In contrast, activation of TLR-9 has been shown to promote a host-protective response. However, whether there is a relationship between the interaction of LPG and TLR-2, on one hand, with the effect of TLR-9, on the other hand, remains unknown. In this study, we report that in-vitro infection of macrophages with a L. major parasite with high expression levels of LPG results in decreased TLR-9 expression compared to infection with a L. major parasite with lower expression levels of LPG. Addition of anti-LPG as well as anti-TLR-2 antibodies prevents this reduction of TLR-9 expression. Also, the addition of purified LPG to macrophages results in a decrease of TLR-9 expression, which is shown to be mediated by transforming growth factor (TGF)-β and interleukin (IL)-10. Finally, in-vitro treatment of macrophages with anti-LPG and/or anti-TLR-2 antibodies before infection reduces the number of amastigotes in macrophages and co-treatment of mice with anti-TLR-2 antibodies and cytosine-phosphate-guanosine (CpG) reduces footpad swelling and parasite load in the draining lymph nodes, accompanied by an interferon (IFN)-γ-predominant T cell response. Thus, for the first time, we show how interactions between LPG and TLR-2 reduce anti-leishmanial responses via cytokine-mediated decrease of TLR-9 expression.

• Authors: S Srivastava, S P Pandey, M K Jha, H S Chandel, B Saha
• Journal: Clinical and experimental immunology (Clin Exp Immunol) Vol. 172 Issue 3 Pg. 403-9 (Jun 2013) ISSN: 1365-2249 [Electronic] England
• PMID: 23600828 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 British Society for Immunology.

Chemical References

• Glycosphingolipids
• IL10 protein, mouse
• Tlr2 protein, mouse
• Tlr9 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptor 9
• Transforming Growth Factor beta
• lipophosphonoglycan
• Interleukin-10
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse

Topics

• Animals
• CpG Islands (immunology)
• Gene Expression
• Glycosphingolipids (genetics, immunology)
• Host-Parasite Interactions (genetics, immunology)
• Immune Tolerance
• Interleukin-10 (genetics, metabolism)
• Leishmania major (genetics, immunology, pathogenicity)
• Leishmaniasis, Cutaneous (genetics, immunology, parasitology, therapy)
• Macrophage Activation
• Macrophages (immunology, parasitology)
• Mice
• Mice, Inbred BALB C
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Toll-Like Receptor 2 (antagonists & inhibitors, genetics, metabolism)
• Toll-Like Receptor 9 (genetics, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)
• Virulence (immunology)