RNA sensing by conventional dendritic cells is central to the development of lupus nephritis

Abstract

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.TLR7 | dendritic cells | SLE | nephritis | autoimmunity

A systems approach to renal inflammation in SLE

“…By contrast CD11c hi dendritic cells express genes associated with regulation of lymphocyte activation and cell death. Similar differences in gene expression of renal macrophages and DCs have been reported in the Sle1.TLR7 model (58). …”

Toll‐Like Receptor 9 Deficiency Breaks Tolerance to RNA‐Associated Antigens and Up‐Regulates Toll‐Like Receptor 7 Protein in Sle1 Mice

“…We also observed increases in CD138+B220− plasma cell numbers (Supplementary Table 2) and a decreased frequency of marginal zone B cells (Supplementary Figure 1A, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.40535/abstract), which are characteristics of lupus models overexpressing TLR‐7 . CD4+ and CD8+ T cells from Sle1 TLR‐9 −/− mice had a more activated phenotype, with higher percentages of CD62L low CD44 high effector memory cells and CD4+ follicular helper T cells, and increased programmed death 1 and inducible costimulator expression, consistent with observations in S le1b TLR‐9 −/− mice and in Sle1 mouse models overexpressing TLR‐7, such as Sle1 Tg7 (Figure E, Supplementary Figures 1B–D, and Supplementary Table 2).…”

“…Gr1 −/low cells represented the majority of the expanding myeloid population (Supplementary Figure 1E) and were further analyzed for CD11c and major histocompatibility complex (MHC) class II expression (Supplementary Figure 1F). Conventional CD11b+ DCs (cDCs) expressing MHC class II, and a possible precursor, which lacks MHC class II, were increased; both were previously characterized in the Sle1 Tg7 model (Supplementary Figure 1F and Supplementary Table 2) . Splenic F4/80+CD64+CD11b intermediate macrophage, CD8+ DC, and pDC numbers, but not frequencies, were increased due to increased cellularity in TLR‐9–deficient Sle1 mice (Supplementary Table 2).…”

Renal-infiltrating CD11c+ cells are pathogenic in murine lupus nephritis through promoting CD4+ T cell responses

“…The similar accumulation of CD11c + cells in the nephritic kidney of both MRL and MRL/lpr mice suggests that the increase of renal‐infiltrating CD11c + cells and their pathogenic functions should be due to the multiple SLE susceptibility loci present in the MRL mouse background, rather than the Fas lpr gene mutation in MRL/lpr mice. While the accumulation and subpopulations of renal‐infiltrating CD11c + cells, especially CD11c + CD11b + DCs, have also been studied in some other lupus‐prone mouse models by other groups , in comparison the renal‐infiltrating CD11c + cells we identified in MRL/lpr mice have shown both similarities and differences. Regarding F4/80 and MHC‐II expression, unlike the three subpopulations (F4/80 + , F4/80 – MHC‐II – and F4/80 – MHC‐II + ) of renal‐infiltrating CD11c + CD11b + cells in SLE 1 transgenic TLR‐7 mice , those in the kidneys of MRL/lpr mice are all F4/80 low MHC‐II + and similar to the renal‐infiltrating CD11c + CD11b + F4/80 low cells identified in NZB/W F 1 mice that express MHC‐II from low to high levels , suggesting that these cells belong to the same population with different activating status.…”

“…While the accumulation and subpopulations of renal‐infiltrating CD11c + cells, especially CD11c + CD11b + DCs, have also been studied in some other lupus‐prone mouse models by other groups , in comparison the renal‐infiltrating CD11c + cells we identified in MRL/lpr mice have shown both similarities and differences. Regarding F4/80 and MHC‐II expression, unlike the three subpopulations (F4/80 + , F4/80 – MHC‐II – and F4/80 – MHC‐II + ) of renal‐infiltrating CD11c + CD11b + cells in SLE 1 transgenic TLR‐7 mice , those in the kidneys of MRL/lpr mice are all F4/80 low MHC‐II + and similar to the renal‐infiltrating CD11c + CD11b + F4/80 low cells identified in NZB/W F 1 mice that express MHC‐II from low to high levels , suggesting that these cells belong to the same population with different activating status. Furthermore, combined with additional markers, these renal‐infiltrating CD11c + cells possessed a surface phenotype of mature monocytes, especially with a high expression of CX 3 CR1, which is consistent with studies in SLE patients where CX 3 CR1 + cells and CD16 + cells are found in the kidney biopsies of patients with active LN .…”