Autocrine Production of IFN-γ by Macrophages Controls Their Recruitment to Kidney and the Development of Glomerulonephritis in MRL/lpr Mice

Abstract

Anti-DNA autoantibody production is a key factor in lupus erythematosus development; nonetheless, the link between glomerular anti-DNA autoantibody deposition and glomerulonephritis development is not understood. To study the inflammatory and destructive processes in kidney, we used IFN-γ+/− MRL/lpr mice which produce high anti-DNA Ab levels but are protected from kidney disease. The results showed that defective macrophage recruitment to IFN-γ+/− mouse kidney was not caused by decreased levels of monocyte chemoattractant protein-1, a chemokine that controls macrophage migration to MRL/lpr mouse kidney. To determine which IFN-γ-producing cell type orchestrates the inflammation pathway in kidney, we transferred IFN-γ+/+ monocyte/macrophages or T cells to IFN-γ−/− mice, which do not develop anti-DNA autoantibodies. The data demonstrate that IFN-γ production by infiltrating macrophages, and not by T cells, is responsible for adhesion molecule up-regulation, macrophage accumulation, and inflammation in kidney, even in the absence of autoantibody deposits. Therefore, in addition to monocyte chemoattractant protein-1, macrophage-produced IFN-γ controls macrophage migration to kidney; the degree of IFN-γ production by macrophages also regulates glomerulonephritis development. Our findings establish the level of IFN-γ secretion by macrophages as a link between anti-DNA autoantibody deposition and glomerulonephritis development, outline the pathway of the inflammatory process, and suggest potential treatment for disease even after autoantibody development.

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

“…Otherwise, blockade of CCR1 could selectively halt interstitial leukocyte recruitment and fibrosis but not glomerular injury in MRL/lpr mice (39). Some published studies demonstrated that CD4ϩ T cells were major infiltrating cells in glomeruli, whereas F4/80ϩ macrophages were predominant in the interstitium of both MRL/lpr mice and lupus-prone NZM2328 mice (40,41). Thus, we reasoned that differential effects of SM934 on autoantibody production and inflammatory leukocyte migration and/or function will result in differential therapeutic effects on glomerular and interstitial inflammation.…”

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

“…Furthermore, IFN-c receptor -/-MRL/lpr mice developed scleroderma-like disease, suggesting a protective role for IFN-c in fibrotic diseases [58]. IFN-c +/-MRL/lpr mice produced high anti-DNA antibody levels but were protected from kidney disease, suggesting a protective role with moderate IFN-c production [59]. Therapeutic benefits from IFN-c production were supported further by Ring et al [60], who demonstrated that IFN-c had a protective role in immunologically mediated glomerulonephritis initiated by foreign antigens.…”

Interferon-γ Augments Acute Macrophage-Mediated Renal Injury Via a Glucocorticoid-Sensitive Mechanism

“…by infiltrating macrophages is critical for the development of macrophage infiltration and development of lupus nephritis in IFN-␥Ϫ/Ϫ MRL/lpr mice (27). Although, whether the IFN-␥ producing cells seen in the kidney 4 mo after adoptive transfer of IFN-␥ ϩ/ϩ Mac-1ϩ spleen cells into IFN-␥Ϫ/Ϫ mice were macrophages or some other cell type(s) arising from the transfer was not determined (27).…”

“…Although, whether the IFN-␥ producing cells seen in the kidney 4 mo after adoptive transfer of IFN-␥ ϩ/ϩ Mac-1ϩ spleen cells into IFN-␥Ϫ/Ϫ mice were macrophages or some other cell type(s) arising from the transfer was not determined (27). IFN-␥ production by NR8383 cells is not a mechanism for increased glomerular recruitment of transferred macrophages in our study since IFN-␥ mRNA was detected by RT-PCR in endotoxin-stimulated NR8383 cells, but not in unstimulated or IFN-␥-stimulated cells (data not shown).…”