Deletion of microRNA-155 reduces autoantibody responses and alleviates lupus-like disease in the Faslpr mouse

MicroRNA-155 (miR-155) regulates antibody responses and subsequent B-cell effector functions to exogenous antigens. However, the role of miR-155 in systemic autoimmunity is not known. Using the death receptor deficient (Fas^lpr) lupus-prone mouse, we show here that ablation of miR-155 reduced autoantibody responses accompanied by a decrease in serum IgG but not IgM anti-dsDNA antibodies and a reduction of kidney inflammation. MiR-155 deletion in Fas^lpr B cells restored the reduced SH2 domain-containing inositol 5′-phosphatase 1 to normal levels. In addition, coaggregation of the Fc γ receptor IIB with the B-cell receptor in miR-155^−/−-Fas^lpr B cells resulted in decreased ERK activation, proliferation, and production of switched antibodies compared with miR-155 sufficient Fas^lpr B cells. Thus, by controlling the levels of SH2 domain-containing inositol 5′-phosphatase 1, miR-155 in part maintains an activation threshold that allows B cells to respond to antigens.MicroRNA-155 (miR-155) plays a critical role in the generation of effective antibody responses to exogenous antigenic challenges in mice (1–3). MiR-155 levels have been reported to be elevated in B but low in T cells from patients with systemic lupus erythamosus (4), yet it is not known whether miR-155 controls autoimmune responses and the expression of related pathology.Mice harboring ubiquitous or B-cell-specific ablation of the death receptor Fas develop a severe lupus-like disease. B-cell-specific deletion of the death receptor (fas^−/−) fas^−/− mice develop an excessive germinal center (GC)-derived IgG autoantibody deposition in their kidneys and succumb to renal failure (5). It has been suggested that loss of tolerance in lpr mice results from the down-regulation of the low-affinity IgG inhibitory receptor FcγRIIB (Fc γ receptor IIB), thereby rendering their B cells incapable of terminating stimulatory signals delivered by autoantigen-containing immune complexes (6–8). However, the mechanisms whereby lack of FcγRIIB engagement would lead to autoimmunity, and whether additional factors contribute to autoimmunity, are still unclear.The SH2 domain-containing inositol 5′-phosphatase 1 (SHIP-1) phosphatase acts downstream of inhibitory cell-surface receptors (9–12), including the FcγRIIB, which is essential in opposing B-cell activation signals in mice and humans (13, 14). FcγRIIB inactivation has been implicated in the development of autoreactive GC B cells and plasma cells (15), as well as in the regulation of the persistence and longevity of bone marrow plasma cells (16). After coligation of the FcγRIIB with the B-cell receptor (BCR), FcγRIIB recruits SHIP-1 to the plasma membrane, where it negatively regulates cell survival, Ca²⁺-dependent effector functions, and ERK activation, thus controlling cell proliferation, anergy, and apoptosis (17–23). As a consequence of these wide-ranging activities, germ-line or B-cell-specific deletion of FcγRIIB or SHIP-1 in mice results in a severe lupus-like disease characterized by high-titer serum IgG antinuclear autoantibodies, lymphadenopathy, splenomegaly, renal failure, and increased mortality (23–27). MiR-155 has been reported to regulate SHIP-1 expression in mammalian myeloid and malignant B cells (28–31). However, it is not known whether SHIP-1 regulation by miR-155 affects GC reactions or peripheral tolerance during a protective immune response or in an autoimmune environment, such as that in Fas^lpr mice.To understand the role of miR-155 in autoimmunity, we crossed Fas^lpr mice with our bic/miR-155^−/− mice to generate miR-155^−/−-Fas^lpr animals. Here we demonstrate that deletion of miR-155 reduced serum IgG but not IgM anti-dsDNA autoantibody levels and kidney damage. Further, we show that the absence of miR-155 derepresses the expression of SHIP-1, thus mitigating B-cell activation, proliferation, and autoimmune responses. We provide evidence that miR-155 could be targeted to control autoimmunity and lupus nephritis.