Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE (Nat Immunol, 2007, 8:487-496)

報告日期: 2007/10/02
報告時間: 16:00/16:50
報告學生: 薛盈彰
講評老師: 葉才明

Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE

Jane Tian, Ana Maria Avalos, Su-Yau Mao, Bo Chen, Kannaki Senthil, Herren Wu, Peggy Parroche, Stacey Drabic, Douglas Golenbock, Cherilyn Sirois, Jing Hua, Ling Ling An, Laurent Audoly, Greg La Rosa, Angelika Bierhaus, Peter Naworth, Ann Marshak-Rothstein, Mary K Crow, Katherine A Fitzgerald, Eicke Latz, Peter A Kiener & Anthony J Coyle

Nature Immunology 8, 487 - 496 (2007)

Speaker: 薛盈彰

Commentator: 葉才明老師

Date: 2007/10/02

Room: 602



Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by self DNA recognized by endosomal localization Toll-like receptor 9 (TLR9). Subsequently, it results in activation of antinuclear B cells and disease progression. However, the mechanisms that mammal-derived self DNA-containing immune complexes activate TLR9 and induce cell activation remain poorly understood. The DNA binding nuclear protein high mobility group

box 1
(HMGB1) is secreted by necrosis cell to induced inflammation. HMGB1 is present in serum of inflammatory disorders such as sepsis and rheumatoid arthritis. Therefore, in this paper the role of HMGB1 in SLE pathogenesis will be invesigated. First, the authors showed that the TLR9 ligand, type A CpG, could bind to HMBG1, and HMBG1-CpG A complexes would activate IFN-α or TNF secretion from plasmacytoid dendritic cells (pDC). Then, decrease of IFN-α production after HMBG1-CpG A complexes stimulation was found in RAGE (receptor for advanced glycation end-products) deficient bone marrow cells. It was also found that RAGE was the surface receptor of HMGB1-CpG A complexes. Furthermore, RAGE-HMGB1-CpG A complexes could enter cell and anchor to the early endosome. After co-transfection of TLR9 and RAGE to HEK293 cell, HMGB1-CpG A induced TLR9 interaction with RAGE. In addition, incubation of PBMCs with 20% plasma from people with lupus enhanced type I IFN expression. However, if human HMGB1 was depleted, the type I IFN expression was suppressed. In conclusion, the authors suggested that binding of HMGB1-CpG A to cell surface receptor RAGE and activation of cytokine production was mediated by TLR9 signal pathway on pDC and B cells in response to DNA which might contribute to autoimmune pathogenesis.



Dumitriu, I.E., Baruah, P., Bianchi, M.E., Manfredi, A.A. & Rovere-Querini, P. Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells. Eur. J. Immunol. 35, 2184–2190 (2005).

Mok, C.C. & Lau, C.S. Pathogenesis of systemic lupus erythematosus. J. Clin. Pathol. 56, 481-490 (2003).