Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus

Abstract

In vitro evidence suggests that plasmacytoid dendritic cells (pDCs) are intimately involved in the pathogenesis of lupus. However, it remains to be determined whether these cells are required in vivo for disease development, and whether their contribution is restricted to hyperproduction of type I IFNs. To address these issues, we created lupus-predisposed mice lacking the IFN regulatory factor 8 (IRF8) or carrying a mutation that impairs the peptide/histidine transporter solute carrier family 15, member 4 (SLC15A4). IRF8-deficient NZB mice, lacking pDCs, showed almost complete absence of anti-nuclear, anti-chromatin, and anti-erythrocyte autoantibodies, along with reduced kidney disease. These effects were observed despite normal B-cell responses to Toll-like receptor (TLR) 7 and TLR9 stimuli and intact humoral responses to conventional T-dependent and -independent antigens. Moreover, Slc15a4 mutant C57BL/6-Fas lpr mice, in which pDCs are present but unable to produce type I IFNs in response to endosomal TLR ligands, also showed an absence of autoantibodies, reduced lymphadenopathy and splenomegaly, and extended survival. Taken together, our results demonstrate that pDCs and the production of type I IFNs by these cells are critical contributors to the pathogenesis of lupus-like autoimmunity in these models. Thus, IRF8 and SLC15A4 may provide important targets for therapeutic intervention in human lupus.E xtensive evidence suggests that type I IFNs are major pathogenic effectors in lupus-associated systemic autoimmunity. A well-documented pattern of expression of type I IFN-inducible genes occurs in peripheral blood mononuclear cells of patients with systemic lupus erythematosus (SLE) (1-3), and reduced disease is observed in some lupus-predisposed mice that either lack the common receptor (IFNAR) for these cytokines (4, 5) or have been treated with IFNAR-blocking antibody (6). Consequently, attention has focused on defining the cell subsets and signaling processes involved in type I IFN production, the mechanisms by which these mediators accelerate disease, and approaches to interfere with these pathogenic events.Early in vitro studies showed that type I IFN production can be induced in normal blood leukocytes by SLE autoantibodies complexed with nucleic acid-containing apoptotic/necrotic cell material, and further work demonstrated that this activity is sensitive to RNase and DNase digestion (7,8). These results were integrated in a more comprehensive scheme following the demonstration that type I IFN induction by these complexes is mediated by the engagement of endosomal Toll-like receptors (TLRs) (9-11). Similarly, antigenic cargo containing nucleic acids was found to promote B-cell proliferation in a TLR9-or TLR7-dependent manner, with this effect enhanced by type I IFN signaling (9, 12, 13). The contribution of nucleic acid-sensing TLRs to systemic autoimmunity was further corroborated by studies in lupus-predisposed mice lacking or overexpressing TLR7 and/or TLR9 (14-20), and in Unc93b1 (3d) mutant mice i...

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification

“…Moreover, IFN-α signaling promotes autoimmune (1), viral (2)(3)(4)(5), and bacterial disease pathogenesis (6). Suppression of IFN-α signaling has demonstrated efficacy in multiple autoimmune mouse models (7)(8)(9) and during influenza viral infection (4,10); however, the mechanism by which sphingosine 1-phosphate receptor 1 (S1PR1) signaling prevents IFN-α amplification during these disease states is currently unknown.…”

Prosurvival Bcl-2 family members reveal a distinct apoptotic identity between conventional and plasmacytoid dendritic cells

“…Conversely, pDCs express TLR-7 and abundant type 1 interferons but lack the ability to present antigen in noninflammatory conditions (7,8). pDCs have been implicated in the pathogenesis of systemic lupus erythematosus (9,10), whereas cDCs are critical for activating killer T cells (CTLs) against Listeria and Plasmodia (1) and immune responses to proteinaceous vaccines (2). The DC subsets have different lifespans (11,12).…”

Interferon Regulatory Factor 8 (IRF8) Interacts with the B Cell Lymphoma 6 (BCL6) Corepressor BCOR

“…IRF8 is highly expressed in mouse and human GCs (15,30) and shares a large number of common target genes in GC B cells, about half of which are also targeted by PU.1 (16). IRF8 has also been implicated in the development of B cell-driven systemic autoimmune diseases in humans and mice (31,32). Finally, several recent studies have identified roles for IRF8 in the pathogenesis of human diffuse large B cell lymphoma (33,34) and probably mouse diffuse large B cell lymphoma as well (15).…”