The system consists of germline-encoded genes, i.e. toll-like receptors (TLRs) 2, complements 3 and lectins 4, which are pattern recognition receptors (PRRs) that discriminate self from pathogen-associated molecular patterns 5. Dendritic cells (DCs) and macrophages (Mϕ) express a variety of PRRs that play important roles in both the innate and adaptive immune responses. Recent reports revealed that TLRs on DCs and Mϕ are involved in sensing various components of pathogens 2, giving rise to cellular inflammatory reactions. C-type

lectin receptors (CLRs) on GDC-0449 concentration DCs and Mϕ also sense pathogens 4. CLRs interact with various kinds of pathogens via carbohydrate recognition domains (CRD), which lead to internalization, degradation and subsequent antigen presentation. In addition, simultaneous triggering of a different set of PRRs has been shown to induce diverse innate immune responses. Much interest has been focused on type II transmembrane CLRs containing a single CRD. Dectin-1 6 and human (h) DC-SIGN (CD209) 7 are the most extensively studied members of this family. Dectin-1 is a major receptor for β-glucan 8, a component of the selleck products cell wall of Candida albicans, Pneumocystis carinii and Aspergillus fumigatus8–12. Microbe-mediated stimulation of Dectin-1 results in cellular oxidative burst and cytokine production through its ITAM and the Syk kinase pathway 13, 14. In addition, Dectin-1 has been shown

to function collaboratively with TLR2 to stimulate cytokine production 15 and Th17/Treg induction 16. hDC-SIGN recognizes mannose and fucose moieties in the

surface of a variety of microbes and viruses, such as Mycobacteria, Leishmania, Salmonella, Candida species, HIV, HCV, dengue virus, CMV, Ebola virus and Sindbis virus (refer to 17). However, pathogens, i.e. HIV and HCV, have however also found ways to subvert and use hDC-SIGN to their advantage 18, 19. Mycobacterium tuberculosis and HIV also target hDC-SIGN in order to upregulate DC production of the immunosuppressive cytokine IL-10 through Raf-1 kinase activation, which induces acetylation of the NF-κB p65 subunit in the presence of co-signaling from TLR4 20. Mice have eight hDC-SIGN homologues 21, 22. One of these homologues, SIGNR1, has been shown to be expressed on particular Mϕ subsets in the marginal zone of the spleen, medulla of the lymph nodes and the peritoneal cavity 23–25 and to possess mannose-binding activities like hDC-SIGN. SIGNR1 recognizes not only various polysaccharides, such as dextran and mannan, but also lipopolysaccharides (LPS) from Gram-negative bacteria (E. coli and Salmonella typhimurium) 23. The physical association of SIGNR1 with the TLR4-MD-2 complex on the cell surface accelerates TLR4 oligomerization upon recognition of the non-reductive end of LPS core on Gram-negative bacteria 26. In addition, SIGNR1 on resident peritoneal macrophages (rpMϕ) and SIGNR1-transfected RAW264.7 cells recognizes zymosan and heat-killed (HK) C.