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

Abstract

Background In people with SLE and in the MRL-Fas lpr 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-Fas lpr mice expressing IL-34 and IL-34 knockout (KO) MRL-Fas lpr 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-Fas lpr 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-Fas lpr 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.

A multi-layered systems approach for renal cell carcinoma

“…It is expressed in several organs, including in tubular cells of the kidney 52 . IL34 supports the growth and survival of primary human monocytes and induces their differentiation into type 2 macrophages 53 IL34 has been linked with autoimmune and inflammatory diseases such as rheumatoid arthritis 53,54 , hepatitis C infection 55 , lupus nephritis 56 , inflammatory bowel disease 57 . It has been linked to chronic kidney injury and kidney graft rejection 52 , and to cancers including osteosarcoma 58 or lung cancer 59 .…”

The Emerging Role of Renal Tubular Epithelial Cells in the Immunological Pathophysiology of Lupus Nephritis

“…Wada et al recently demonstrated robust RTEC expression of IL-34 in biopsies from LN patients and MRL-Fas lpr lupus mice, with significant associations between expression levels and disease activity. Further mechanistic investigations using this lupus mouse model showed that IL-34 enhances intrarenal macrophage accumulation/proliferation, leading to macrophage-mediated RTEC apoptosis ( 52 ). These findings identify IL-34 as a novel therapeutic target of RTEC-mediated immunopathogenesis in LN.…”

Potential for Targeting Myeloid Cells in Controlling CNS Inflammation

“…However, as mentioned earlier, elevated levels of M-CSF are also observed in different pathologies. There are multiple publications linking M-CSF/IL-34 and CSF-1R signaling in models of arthritis ( 113 – 116 ), diabetes ( 117 ), systemic lupus erythematosus ( 85 , 118 ), cancer ( 119 – 121 ), amyotrophic lateral sclerosis ( 122 ), Parkinson's disease ( 123 ), and Alzheimer's disease ( 124 – 126 ). In an effort to determine the role of M-CSF/IL-34 and CSF-1R signaling in MS, different groups used potent c-fms tyrosine kinase inhibitors, which block M-CSF signaling.…”