Abstract
A pivotal role of type I interferons in systemic lupus erythematosus (SLE) is widely accepted. Type III interferons (IFN-λ) however, the most recently discovered cytokines grouped within the interferon family, have not been extensively studied in lupus disease models yet. Growing evidence suggests a role for IFN-λ in regulating both innate and adaptive immune responses, and increased serum concentrations have been described in multiple autoimmune diseases including SLE. Using the pristane-induced lupus model, we found that mice with defective IFN-λ receptors (Ifnlr1−/−) showed increased survival rates, decreased lipogranuloma formation and reduced anti-dsDNA autoantibody titers in the early phase of autoimmunity development compared to pristane-treated wild-type mice. Moreover, Ifnlr1−/− mice treated with pristane had reduced numbers of inflammatory mononuclear phagocytes and cNK cells in their kidneys, resembling untreated control mice. Systemically, circulating B cells and monocytes (CD115+Ly6C+) were reduced in pristane-treated Ifnlr1−/− mice. The present study supports a significant role for type III interferons in the pathogenesis of pristane-induced murine autoimmunity as well as in systemic and renal inflammation. Although the absence of type III interferon receptors does not completely prevent the development of autoantibodies, type III interferon signaling accelerates the development of autoimmunity and promotes a pro-inflammatory environment in autoimmune-prone hosts.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disorder presenting with a large variety of clinical symptoms and mostly affects women of childbearing age [1,2,3]
Ifnlr1+/+ (WT) and Ifnlr1−/− mice were intraperitoneally injected with 500 μL of pristane survived, whereas 70an%dero6fmthonethWs (TFigmuriec1eAd).iAedll owf tihtehIifnnlrt1h−/−emfiicrest(nm= o10n/1t0h) asufrtveivreidn, jection (Figure 1B)
EExxppereimriemntael ndetsaigl nd, esusrivgivna,l asnudravuitvoiamlmaunndityapuartaomimetemrs. u(An)iWtyT panadrIafnmlr1e−/t−emrisc.ee WintrTapaernitdonIefanllylr1−/− mice injected with 500 μL of pristane and sacrificed after 6 months
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disorder presenting with a large variety of clinical symptoms and mostly affects women of childbearing age [1,2,3]. Type III IFN levels correlated with SLE Disease Activity Index scores and anti-double-stranded DNA (dsDNA) autoantibody titers [25,26,27,28,29]. Chronic application of imiquimod induces skin inflammatory disease, which results in systemic autoimmunity following the likely disruption of the epidermal barrier, and is used as a murine model for human psoriasis, and for SLE because of the observed development of anti-dsDNA autoantibodies and systemic organ damage including glomerulonephritis [31,32]. Lupus nephritis patients do not always have skin disease To address this conundrum, we used the well-established pristane-induced model of murine lupus in Ifnlr1-deficient mice. The role of type III IFN has not been investigated in this murine lupus model yet
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