Sialoadhesin deficiency does not influence the severity of lupus nephritis in New Zealand Black x New Zealand White F1 mice

Abstract

IntroductionSystemic lupus erythematosus (SLE) is a chronic inflammatory condition with multisystem involvement. One of the key features of the disease is the upregulation of type I interferons, resulting in the so-called “interferon signature”. Recent flow cytometric and transcriptomic studies identified Sialoadhesin (Sn, CD169) as an important interferon-induced blood monocyte biomarker in diseased patients. To investigate a potential causative role of Sn in SLE, we generated NZBWF1 (New Zealand Black x New Zealand White F1) mice lacking Sn and compared onset and progression of disease with NZBWF1 expressing normal levels of Sn.MethodsSn expression in renal tissues of pre-diseased and diseased NZBWF1 mice was evaluated by Quantitative real time PCR (QPCR) and immunohistochemistry. Sn−/− NZBWF1 mice were generated by speed congenics. Disease severity of Sn+/+ and Sn−/− NZBWF1 mice was assessed by serum immunoassays, flow cytometry, light microscopy and immunohistochemistry.ResultsRenal tissues from proteinuric NZBWF1 mice exhibited a significant upregulation of Sn mRNA and protein expression following disease onset. Further immunohistochemical analysis showed that Sn+ macrophages assumed a distinct periglomerular distribution and, unlike CD68+ macrophages, were not present within the glomeruli. Analysis of disease severity in Sn−/− and Sn+/+ NZBWF1 mice revealed no significant differences in the disease progression between the two groups although Sn-deficient mice showed a more rapid onset of proteinuria.ConclusionsThese data confirm a positive correlation of Sn with disease activity. However, Sn deficiency does not have a significant effect on the severity and progression of lupus nephritis in the NZBWF1 mouse model.

The pathogenesis, diagnosis and treatment of lupus nephritis

“…Sn was also thought to have a functional component, as its deficiency leads to amelioration of murine autoimmune neuropathy [22]. However, Kidder et al demonstrated that in NZB/NZW F1 mice, Sn-deficiency did not reduce LN severity or delay disease progression [23•]. Therefore, while Sn may have a role as a biomarker for disease severity in LN, it will not necessarily serve as a future therapeutic target.…”

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

“…Whereas CD169 deficiency is sufficient to ameliorate murine autoimmune neuropathy, suggesting a functional contribution of this molecule to autoimmune pathologies [68], LN severity and disease progression in a murine model of SLE were unaffected by CD169 deficiency [69]. However, in SLE, CD169-expressing monocytes within the glomeruli correlate with LN disease severity [70], suggesting a utility for this molecule not as a therapeutic target for, but as a biomarker of, LN disease severity [71].…”

Lectin Receptors Expressed on Myeloid Cells

“…Many of the above disease associations may reflect exposure of macrophages to interferons rather than being causally related. Indeed, in the BWF1 murine model of spontaneous systemic lupus erythematosus, there was no influence of Sn deficiency on disease severity (45). However, in mouse models of inherited neuropathy (46)(47)(48), autoimmune uveoretinitis (49), and experimental allergic encephalomyelitis (50), Sn-deficient mice exhibited reduced inflammation accompanied by reduced levels of T-cell and macrophage activation.…”