Interferon Regulatory Factor-5 Deficiency Ameliorates Disease Severity in the MRL/lpr Mouse Model of Lupus in the Absence of a Mutation in DOCK2

Abstract

Interferon regulatory factor 5 (IRF5) polymorphisms are strongly associated with an increased risk of developing the autoimmune disease systemic lupus erythematosus. In mouse lupus models, IRF5-deficiency was shown to reduce disease severity consistent with an important role for IRF5 in disease pathogenesis. However these mouse studies were confounded by the recent demonstration that the IRF5 knockout mouse line contained a loss-of-function mutation in the dedicator of cytokinesis 2 (DOCK2) gene. As DOCK2 regulates lymphocyte trafficking and Toll-like receptor signaling, this raised the possibility that some of the protective effects attributed to IRF5 deficiency in the mouse lupus models may instead have been due to DOCK2 deficiency. We have therefore here evaluated the effect of IRF5-deficiency in the MRL/lpr mouse lupus model in the absence of the DOCK2 mutation. We find that IRF5-deficient (IRF5−/−) MRL/lpr mice develop much less severe disease than their IRF5-sufficient (IRF5+/+) littermates. Despite markedly lower serum levels of anti-nuclear autoantibodies and reduced total splenocyte and CD4+ T cell numbers, IRF5−/− MRL/lpr mice have similar numbers of all splenic B cell subsets compared to IRF5+/+ MRL/lpr mice, suggesting that IRF5 is not involved in B cell development up to the mature B cell stage. However, IRF5−/− MRL/lpr mice have greatly reduced numbers of spleen plasmablasts and bone marrow plasma cells. Serum levels of B lymphocyte stimulator (BLyS) were markedly elevated in the MRL/lpr mice but no effect of IRF5 on serum BLyS levels was seen. Overall our data demonstrate that IRF5 contributes to disease pathogenesis in the MRL/lpr lupus model and that this is due, at least in part, to the role of IRF5 in plasma cell formation. Our data also suggest that combined therapy targeting both IRF5 and BLyS might be a particularly effective therapeutic approach in lupus.

Interferon regulatory factor 5 in human autoimmunity and murine models of autoimmune disease

“…This led to conflicting results within the field, including data regarding Type I IFN and antibody production (152), and led to the necessity for rederivation of many Irf5 -/-colonies in order to gain confidence in observed phenotypes -particularly those associated with B-cells. Of note, the observations described for IRF5 in the MRL/lpr model of SLE have been verified as independent of Dock2 mutations (153). Irf5 -/-mouse colonies should therefore now be routinely screened for Dock2 mutations.…”

IRF5 Deficiency Ameliorates Lupus but Promotes Atherosclerosis and Metabolic Dysfunction in a Mouse Model of Lupus-Associated Atherosclerosis

“…We hypothesized that IRF5 deficiency would reduce atherosclerosis severity in the context of lupus for two main reasons. Firstly, the inflammation due to the active autoimmune process is thought to contribute to the premature atherosclerosis in SLE (2) and previous studies in other lupus mouse models suggested that IRF5 deficiency would reduce the active autoimmune process (27-32). Secondly, atherosclerosis itself, independently of systemic autoimmune disease, is driven by a Th1-skewed chronic inflammatory process in which M1-type macrophages play a dominant role (11), and IRF5 has been shown to promote both Th1 responses and M1-type macrophage development (25, 26).…”

“…IRF5 promotes T helper 1 (Th1)/Th17-type immune responses and LPS-induced M1 macrophage polarization (25, 26). IRF5 deficiency ameliorates disease in a number of murine lupus models (27-32). For these reasons, IRF5 is being considered as a potential therapeutic target in SLE and other autoimmune diseases as well as in other inflammatory conditions such as post-myocardial infarction healing (14, 33).…”

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Activates Type I Interferon Signals in Lupus Nephritis

“…Interferon regulatory factor 5 (IRF-5) is a member of the IRF family of transcription factors that induces the expression of type I IFN and IFN-inducible genes [ 28 – 30 ]. In IRF5 −/− MRL/lpr mice, IFN α and autoantibody production were markedly reduced, and glomerulonephritis was much improved [ 31 , 32 ].…”