Toll-like receptor (TLR) signaling plays a critical role in innate and adaptive immune responses and must be tightly controlled. TLR4 uses LPS binding protein, MD-2, and CD14 as accessories to respond to LPS. We therefore investigated the presence of an analagous soluble cofactor that might assist in the recruitment of CpG oligonucleotides (CpG-ODNs) to TLR9. We report the identification of granulin as an essential secreted cofactor that potentiates TLR9-driven responses to CpG-ODNs. Granulin, an unusual cysteine-rich protein, bound to CpG-ODNs and interacted with TLR9. Macrophages from granulin-deficient mice showed not only impaired delivery of CpG-ODNs to endolysosomal compartments, but also decreased interaction of TLR9 with CpG-ODNs. As a consequence, granulin-deficient macrophages showed reduced responses to stimulation with CpG-ODNs, a trait corrected by provision of exogenous granulin. Thus, we propose that granulin contributes to innate immunity as a critical soluble cofactor for TLR9 signaling.
Bibliographical noteFunding Information:
We thank A.M. Avalos and C.C. Lee for critical reading of the manuscript and S.-J. Ha (Yonsei University, Seoul, South Korea) for the generous gifts of the following antibodies: anti-MHC class I antigen, anti-MHC class II antigen, anti-CD40, anti-CD80, and anti-CD86 for FACS analysis. This study was supported by grants from Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0009203), Korea research foundation grant funded by the Korean Government (KRF-2007-357-C00086), the Yonsei University Research Fund of 2010, and a Landon Clay fellowship (to B.P.), NIH and Novartis (to H.L.P.), Novartis (to L.B.), the Yonsei University Research Fund of 2010 (to S.L.), and the Charles A. King Trust, Bank of America, Co-\Trustee (to M.M.B.).
All Science Journal Classification (ASJC) codes
- Immunology and Allergy
- Infectious Diseases