Immunofluorescence staining revealed less IgG staining in the glomeruli of miR-155?/?-mice compared with the large amounts of IgG seen in kidneys (Fig. reduced SH2 domain-containing inositol 5-phosphatase 1 to normal levels. In addition, coaggregation of the Fc receptor IIB with the B-cell receptor in miR-155?/?-B cells resulted in decreased ERK activation, proliferation, and production of switched antibodies compared with miR-155 sufficient 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 (1C3). MiR-155 levels have been reported to TAS-114 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 TAS-114 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 (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 mice results from the down-regulation of the low-affinity IgG inhibitory receptor FcRIIB (Fc receptor IIB), thereby rendering their B cells incapable of terminating stimulatory signals delivered by autoantigen-containing immune complexes (6C8). However, the mechanisms whereby lack of FcRIIB 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 (9C12), including the FcRIIB, which is essential in opposing B-cell activation signals in mice and humans (13, 14). FcRIIB inactivation has been implicated in the development of autoreactive GC B cells and plasma cells (15), as well as in the regulation of the TAS-114 persistence and longevity of bone TAS-114 marrow plasma cells (16). After coligation of the FcRIIB with the B-cell receptor (BCR), FcRIIB 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 (17C23). As a consequence of these wide-ranging activities, germ-line or B-cell-specific deletion of FcRIIB 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 (23C27). MiR-155 has been reported to regulate SHIP-1 expression in mammalian myeloid and malignant B cells (28C31). However, it is not known whether SHIP-1 regulation by miR-155 affects GC reactions or peripheral tolerance during a protective TAS-114 immune response or in an autoimmune environment, such as that in mice. To understand the role of miR-155 in autoimmunity, we crossed mice with our 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. Results Ablation of miR-155 Mitigates Splenomegaly in the Mouse. B-cell-specific or ubiquitous inactivation of Fas leads to early death preceded by a lymphoproliferative disorder manifested as splenomegaly and lymphadenopathy (5, 32). Compared with the aged-matched group (mean size: 0.432 0.01 g), miR-155?/?-mice had a 2.8-fold reduction in their spleen size (mean size: 0.153 0.05 g, 0.0001, Fig. 1and Fig. S1). The smaller spleen size of miR-155?/?-mice was accompanied by a 2.3-fold lower total number of cells in this tissue compared with the mice (mean 1.4 108 vs. 3.2 108, 0.0019, Fig. 1spleen (Fig. 1 and mice had smaller peripheral lymph nodes (pLNs); however, the degree of reduction in Mouse monoclonal to RAG2 their size varied considerably. We did not observe a change in the frequency of the unusual peripheral CD4?CD8? T cells in miR-155?/?-mice compared with mice (Fig. S2) (32). Overall, these data show that targeting of miR-155 limits the development of splenomegaly and lymphadenopathy in mice. Open in a separate window Fig. 1. Ablation of miR-155 alleviates splenomegaly in the mouse. Results were obtained from aged mice (10-12 mo old). WT.