IL-34–Dependent Intrarenal and Systemic Mechanisms Promote Lupus Nephritis in MRL-Faslpr Mice

Significance Statement Macrophages and autoantibodies play a central role in the pathology of lupus nephritis in patients with lupus and in the MRL- Faslpr mouse model. The authors demonstrate that IL-34 and its two receptors, cFMS and PTPRZ, are upregulated in the kidney with advancing nephritis in MRL- Faslpr mice. Genetically deleting IL-34 in these mice suppresses nephritis and the systemic illness via macrophage- and autoantibody-mediated mechanisms within and outside of the kidney. The authors also found that patients with lupus nephritis have elevated IL-34 in serum and urine; intrarenal and systemic expression of IL-34, cFMS, and PTPRZ similar to that displayed in MRL- Faslpr mice; and IL-34 expression that correlates with histopathologic index of disease activity. These findings suggest that IL-34 is a promising novel therapeutic target for patients with lupus nephritis. Background In people with SLE and in the MRL- Faslpr 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. Methods To investigate whether IL-34–dependent intrarenal and systemic mechanisms promote lupus nephritis, we compared lupus nephritis and systemic illness in MRL- Faslpr mice expressing IL-34 and IL-34 knockout (KO) MRL- Faslpr mice. We also assessed expression of IL-34 and the cFMS and PTPRZ receptors in patients with lupus nephritis. Results Intrarenal IL-34 and its two receptors increase during lupus nephritis in MRL- Faslpr mice. In knockout mice lacking IL-34, nephritis and systemic illness are suppressed. IL-34 fosters intrarenal macrophage accumulation via monocyte proliferation in bone marrow (which increases circulating monocytes that are recruited by chemokines into the kidney) and via 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- Faslpr lupus mouse model. Moreover, expression of IL-34 in TECs correlates with disease activity. Conclusions IL-34 is a promising novel therapeutic target for patients with lupus nephritis.