TY - JOUR
T1 - RNA sensing by conventional dendritic cells is central to the development of lupus nephritis
AU - Celhar, Teja
AU - Hopkins, Richard
AU - Thornhill, Susannah I.
AU - De Magalhaes, Raquel
AU - Hwang, Sun Hee
AU - Lee, Hui Yin
AU - Yasuga, Hiroko
AU - Jones, Leigh A.
AU - Casco, Jose
AU - Lee, Bernett
AU - Thamboo, Thomas P.
AU - Zhou, Xin J.
AU - Poidinger, Michael
AU - Connolly, John E.
AU - Wakeland, Edward K.
AU - Fairhurst, Anna Marie
PY - 2015/11/10
Y1 - 2015/11/10
N2 - Glomerulonephritis is a common and debilitating feature of systemic lupus erythematosus (SLE). The precise immune mechanisms that drive the progression from benign autoimmunity to glomerulonephritis are largely unknown. Previous investigations have shown that a moderate increase of the innate Toll-like receptor 7 (TLR7) is sufficient for the development of nephritis. In these systems normalization of B-cell TLR7 expression or temporal depletion of plasmacytoid dendritic cells (pDCs) slow progression; however, the critical cell that is responsible for driving full immunopathology remains unidentified. In this investigation we have shown that conventional DC expression of TLR7 is essential for severe autoimmunity in the Sle1Tg7 model of SLE. We show that a novel expanding CD11b+ conventional DC subpopulation dominates the infiltrating renal inflammatory milieu, localizing to the glomeruli. Moreover, exposure of human myeloid DCs to IFN-α or Flu increases TLR7 expression, suggesting they may have a role in self-RNA recognition pathways in clinical disease. To our knowledge, this study is the first to highlight the importance of conventional DC-TLR7 expression for kidney pathogenesis in a murine model of SLE.
AB - Glomerulonephritis is a common and debilitating feature of systemic lupus erythematosus (SLE). The precise immune mechanisms that drive the progression from benign autoimmunity to glomerulonephritis are largely unknown. Previous investigations have shown that a moderate increase of the innate Toll-like receptor 7 (TLR7) is sufficient for the development of nephritis. In these systems normalization of B-cell TLR7 expression or temporal depletion of plasmacytoid dendritic cells (pDCs) slow progression; however, the critical cell that is responsible for driving full immunopathology remains unidentified. In this investigation we have shown that conventional DC expression of TLR7 is essential for severe autoimmunity in the Sle1Tg7 model of SLE. We show that a novel expanding CD11b+ conventional DC subpopulation dominates the infiltrating renal inflammatory milieu, localizing to the glomeruli. Moreover, exposure of human myeloid DCs to IFN-α or Flu increases TLR7 expression, suggesting they may have a role in self-RNA recognition pathways in clinical disease. To our knowledge, this study is the first to highlight the importance of conventional DC-TLR7 expression for kidney pathogenesis in a murine model of SLE.
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U2 - 10.1073/pnas.1507052112
DO - 10.1073/pnas.1507052112
M3 - Article
C2 - 26512111
AN - SCOPUS:84946762351
SN - 0027-8424
VL - 112
SP - E6195-E6204
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -