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Abstract
BackgroundA majority of autoimmune diseases, including systemic lupus erythematosus (SLE), occur predominantly in females. Recent studies have identified specific dysregulated microRNAs (miRNAs) in both human and murine lupus, implying an important contribution of these miRNAs to lupus pathogenesis. However, to date, there is no study that examined sex differences in miRNA expression in immune cells as a plausible basis for sex differences in autoimmune disease. This study addresses this aspect in NZB/WF1 mice, a classical murine lupus model with marked female bias, and further investigates estrogen regulation of lupus-associated miRNAs.MethodsThe Taqman miRNA assay system was used to quantify the miRNA expression in splenocytes from male and female NZB/WF1 mice at 17–18, 23, and 30 weeks (wks) of age. To evaluate potential estrogen's effect on lupus-associated miRNAs, 6-wk-old NZB/WF1 male mice were orchidectomized and surgically implanted with empty (placebo) or estrogen implants for 4 and 26 wks, respectively. To assess the lupus status in the NZB/WF1 mice, serum anti-dsDNA autoantibody levels, proteinuria, and renal histological changes were determined.ResultsThe sex differences in the expression of lupus-associated miRNAs, including the miR-182-96-183 cluster, miR-155, miR-31, miR-148a, miR-127, and miR-379, were markedly evident after the onset of lupus, especially at 30 wks of age when female NZB/WF1 mice manifested moderate to severe lupus when compared to their male counterparts. Our limited data also suggested that estrogen treatment increased the expression of aforementioned lupus-associated miRNAs, with the exception of miR-155, in orchidectomized male NZB/WF1 mice to a similar level in age-matched intact female NZB/WF1 mice. It is noteworthy that orchiectomy, itself, did not affect the expression of lupus-associated miRNAs.ConclusionTo our knowledge, this is the first study that demonstrated sex differences in the expression of lupus-associated miRNAs in splenocytes, especially in the context of autoimmunity. The increased expression of lupus-associated miRNA in female NZB/WF1 mice and conceivably in estrogen-treated orchidectomized male NZB/WF1 mice was associated with lupus manifestation. The notable increase of lupus-associated miRNAs in diseased, female NZB/WF1 mice may be a result of both lupus manifestation and the female gender.
Highlights
A majority of autoimmune diseases, including systemic lupus erythematosus (SLE), occur predominantly in females
Given that there are marked sex differences in susceptibility to lupus, are there comparable sex differences in the expression of lupus-associated miRNAs? Second, since estrogen accelerates lupus in male NZB/WF1 mice, does estrogen treatment promote the expression of lupus-associated miRNAs? Our study clearly showed that female NZB/WF1 mice displayed increased expression levels of lupus-associated miRNAs after the onset of lupus when compared to age-matched males
Before the onset of lupus, male and female NZB/WF1 mice have comparable levels of lupus-associated miRNAs In our previous study where we utilized only female NZB/WF1 mice, we reported that a set of miRNAs including the miR-96-182-183 cluster, miR-155, miR-31, miR-127, and miR-379 were upregulated only in the splenocytes from diseased 36–40-wk-old (8–9 months) female NZB/WF1 mice, but not in the splenocytes from the pre-diseased 16–18-wk-old (3–4 months) NZB/WF1 mice when compared to those in the control NZW mice [34]
Summary
A majority of autoimmune diseases, including systemic lupus erythematosus (SLE), occur predominantly in females. To date, there is no study that examined sex differences in miRNA expression in immune cells as a plausible basis for sex differences in autoimmune disease This study addresses this aspect in NZB/WF1 mice, a classical murine lupus model with marked female bias, and further investigates estrogen regulation of lupus-associated miRNAs. Sex differences in gene expression have physiological and pathological implications. Much attention has been focused on the epigenetic regulation of gene expression in the context of physiological and pathological conditions Epigenetic mechanisms such as DNA methylation, histone modification, and microRNAs (miRNAs) have been proposed to understand sex differences in gene expression and in susceptibility to a broad range of human diseases including autoimmune diseases such as lupus [1,4,5,6,7]
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