CD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis

Abstract

Dendritic cells (DCs) are critical for immune homeostasis. To target DCs, we generated a mouse line with Flip deficiency in cells that express cre under the CD11c-promoter (CD11c-Flip-KO). CD11c-Flip-KO mice spontaneously develop erosive, inflammatory arthritis, resembling rheumatoid arthritis, which is dramatically reduced when these mice are crossed with Rag−/− mice. The CD8α+ DC subset is significantly reduced, along with alterations in NK cells and macrophages. Autoreactive CD4+ T cells and autoantibodies specific for joint tissue are present and arthritis severity correlates with the number of autoreactive CD4+ T cells and plasmablasts in the joint draining lymph nodes. Reduced T regulatory cells (Tregs) inversely correlate with arthritis severity, and the transfer of Tregs ameliorates arthritis. This KO line identifies a model that will permit in depth interrogation of the pathogenesis of rheumatoid arthritis, including the role of CD8α+ DCs and other cells of the immune system.

Necroptosis of Dendritic Cells Promotes Activation of γδ T Cells

“…As such, c-FLIP expression may be central to the regulation of inflammatory versus tolerogenic DC function. This is consistent with findings in mice in which c-FLIP was deleted in DC, resulting in reduced numbers of DC, consistent with the requirement of c-FLIP for their survival [22]. Of particular interest was that these mice spontaneously developed autoreactive T cells and inflammatory arthritis.…”

The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases

“…Although arthritis has not been examined in myeloid cell-specific FLIP-deficient mice, a study published in 2015 reported that targeted deletion of FLIP in both the CD8 + and CD11b − DC compartments of mice promotes the spontaneous development of an erosive inflammatory arthritis that resembles RA and is accompanied by the production of autoantibodies to joint antigens 100 . Prior to the onset of arthritis, DC populations (in particular CD8 + DCs) are substantially reduced in the thymus, spleen and lymph nodes 100 .…”

“…Prior to the onset of arthritis, DC populations (in particular CD8 + DCs) are substantially reduced in the thymus, spleen and lymph nodes 100 . Although DC-specific FLIP -knockout mice are lymphopenic, autoreactive CD4 + T cells are detected, suggesting that these cells might participate in the propagation of arthritis 100 .…”

The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis

“…Loss of FLIP in the conventional CD8 + and CD11b − dendritic cell compartments ( CD11c cre Flip flox/flox ) promotes spontaneous development of an erosive inflammatory arthritis accompanied by autoantibodies to joint antigens that resembles another autoimmune disorder, rheumatoid arthritis [131]. Prior to the onset of arthritis, the dendritic cell populations, CD8 + dendritic cells in particular, are significantly decreased in the thymus, spleen, and lymph nodes [131].…”

“…Prior to the onset of arthritis, the dendritic cell populations, CD8 + dendritic cells in particular, are significantly decreased in the thymus, spleen, and lymph nodes [131]. Although CD11c cre Flip flox/flox mice are lymphopenic, autoreactive CD4 + T cells are detected and correlate with reduced regulatory T cell numbers [131]. Another group reported that CD11c cre Flip flox/flox mice develop neutrophilia, owing to excess availability of G-CSF, and splenomegaly.…”