IL-34-Dependent Intrarenal and Systemic Mechanisms Promote Lupus Nephritis in MRL-<i>Fas^lpr</i> Mice.

Abstract

In people with SLE and in the MRL-<i>Fas^lpr</i> lupus mouse model, macrophages and autoantibodies are central to lupus nephritis. IL-34 mediates macrophage survival and proliferation, is expressed by tubular epithelial cells (TECs), and binds to the cFMS receptor on macrophages and to a newly identified second receptor, PTPRZ. To investigate whether IL-34-dependent intrarenal and systemic mechanisms promote lupus nephritis, we compared lupus nephritis and systemic illness in MRL-<i>Fas^lpr</i> mice expressing IL-34 and IL-34 knockout (KO) MRL-<i>Fas^lpr</i> mice. We also assessed expression of IL-34 and the cFMS and PTPRZ receptors in patients with lupus nephritis. Intrarenal IL-34 and its two receptors increase during lupus nephritis in MRL-<i>Fas^lpr</i> mice. In knockout mice lacking IL-34, nephritis and systemic illness are suppressed. IL-34 fosters intrarenal macrophage accumulation <i>via</i> monocyte proliferation in bone marrow (which increases circulating monocytes that are recruited by chemokines into the kidney) and <i>via</i> intrarenal macrophage proliferation. This accumulation leads to macrophage-mediated TEC apoptosis. We also found suppression of circulating autoantibodies and glomerular antibody deposits in the knockout mice. This is consistent with fewer activated and proliferating intrarenal and splenic B cells in mice lacking IL-34, and with our novel discovery that PTPRZ is expressed by macrophages, B and T cells. These findings appear translatable to human patients with lupus nephritis, whose expression of IL-34, cFMS, and PTPRZ is similar to that seen in the MRL-<i>Fas^lpr</i> lupus mouse model. Moreover, expression of IL-34 in TECs correlates with disease activity. IL-34 is a promising novel therapeutic target for patients with lupus nephritis.