Role of microRNA-15a in autoantibody production in interferon-augmented murine model of lupus

Abstract

MicroRNAs (miRNAs) are involved in the regulation of immunity via targeting of mRNA encoding immune response elements. In this report, alterations in the expression of microRNAs as autoantibody levels increase was investigated. The (NZB X NZW) F1 or B/W mouse model of systemic lupus erythematosus (SLE) naturally has increased autoantibodies with aging. IFNalpha (type I IFN) accelerates B/W disease, however, the effects of a related IFN, IFNlambda, which is a type III IFN, is largely unknown. The purpose of the study was to investigate the relationship between IFN-accelerated disease, microRNAs, immunoregulatory B cell subsets and autoantibody production in the autoimmune-prone environment in vivo. B/W mice received osmotic pumps to chronically deliver IFNα and IFNλ for up to 16 weeks. Urine protein level was monitored weekly by urine strips and proteinuria was used as the disease marker. Splenic cells were taken for flow analysis of B cell subsets and levels of microRNAs determined. Plasma were analyzed for autoantibodies and microRNA levels. As a result of treatment, IFNα accelerated proteinuria in a dose dependent manner, while IFNλ single treatment did not show a significant effect, but greatly enhanced low dose IFNα effects in the combination treatment. Both the splenic cellular and plasma miR-15a were elevated in diseased compared to pre-diseased mice as well as autoantibody levels. Autoantibodies and miR-15a levels were significantly correlated. The immunosuppressive B subpopulation, B-10, was reduced following IFNα treatment. In addition in diseased mice, B-10 versus B-2 ratios were reduced in IFN-treated B/W compared to the control PBS treated group. In all B/W the miR-15a was highly expressed in the B-10 subset and this increased with disease development, suggesting that miR-15a has a specific negative effect on the B-10 subpopulation. In conclusion, our data support the involvement of elevated miR-15a in autoimmune disease development in B/W mice and suggest that decreasing this microRNA might be beneficial in B/W mice.

MicroRNAs in the key events of systemic lupus erythematosus pathogenesis

“…96 ), all pathogenetic modes of mirs regulation of iFN type i expression require further study. Whereas iFN type i has been established as the main contributor to sle pathogenesis 97 , it is not surprising that the expression of mir-146a in pBmcs of sle patients negatively correlates with disease activity and severity of renal involvement 94,98 . The other cells of innate immunity, macrophages, display deregulated phenotypes and functions in sle patients.…”

The pathogenesis, diagnosis and treatment of lupus nephritis

“…IFN treatment elevated miR-15a levels, which in turn correlated with lower levels of regulatory B cell subpopulations, particularly B-10. The authors concluded that IFN-induced miR-15a overexpression may have a specific negative regulatory effect on this B cell subpopulation [19]. …”

The role of microRNAs in B-cell development and function

“…Notably, miR-15a was highly expressed in the immunosuppressive B-cell subset (B-10). 38 These results suggest that miR-15a induced a loss of regulatory B cells by targeting the antiapoptotic protein Bcl-2, which in turn led to enhanced autoantibody production by autoreactive B cells. 38 The most common genomic aberration in B-cell chronic lymphocytic leukemia is the deletion of the human chromosomal region 13q14, corresponding to the mouse chromosomal region 14qC3, which harbors the miR-15a/miR-16-1 cluster.…”

“…38 These results suggest that miR-15a induced a loss of regulatory B cells by targeting the antiapoptotic protein Bcl-2, which in turn led to enhanced autoantibody production by autoreactive B cells. 38 The most common genomic aberration in B-cell chronic lymphocytic leukemia is the deletion of the human chromosomal region 13q14, corresponding to the mouse chromosomal region 14qC3, which harbors the miR-15a/miR-16-1 cluster. In a recent in vivo mouse study, the loss of the miR-15a/16-1 cluster was shown to accelerate the proliferation of B lymphocytes, resulting in a B-cell autonomous lymphoproliferative disorder.…”