Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus

Abstract

Type III IFN lambdas (IFN-λ) have recently been described as important mediators of immune responses at barrier surfaces. However, their role in autoimmune diseases such as systemic lupus erythematosus (SLE), a condition characterized by aberrant type I IFN signaling, has not been determined. Here, we identify a nonredundant role for IFN-λ in immune dysregulation and tissue inflammation in a model of TLR7-induced lupus. IFN-λ protein is increased in murine lupus and IFN-λ receptor (Ifnlr1) deficiency significantly reduces immune cell activation and associated organ damage in the skin and kidneys without effects on autoantibody production. Single-cell RNA sequencing in mouse spleen and human peripheral blood revealed that only mouse neutrophils and human B cells are directly responsive to this cytokine. Rather, IFN-λ activates keratinocytes and mesangial cells to produce chemokines that induce immune cell recruitment and promote tissue inflammation. These data provide insights into the immunobiology of SLE and identify type III IFNs as important factors for tissue-specific pathology in this disease.

Differential expression of interferon-lambda receptor 1 splice variants determines the magnitude of the antiviral response induced by interferon-lambda 3 in human immune cells

“…Limited data has been published measuring ISG induction by IFN-λs in human neutrophils. Human neutrophils responded~20-fold less than mouse neutrophils to IFN-λ2 [20], and IFIT1 was not induced in human neutrophils after IFN-λ1 treatment [75]. IFN-λ3 may induce greater ISG levels in neutrophils in vivo because neutrophils survive longer than the 5 hour time point used in the current study.…”

Characterization of autoantibodies and cytokines related to cutaneous lupus erythematosus

“…Skin damage was significantly attenuated in a murine lupus model with IFN-λ receptor deficiency. 11,12 Together, these data suggest that IFN-λ1 plays a critical role in lupus skin damages. 11,13…”

COVID-19 and emerging viral infections: The case for interferon lambda

“…The main function of IFN-λ is to prevent viral infection by establishing an antiviral state and, if infected, to slow viral replication and dissemination. In contrast to IFNAR, the IFNLR is largely absent on resting immune cells in humans and mice (with the notable exception of neutrophils [Blazek et al, 2015;Broggi et al, 2017;Espinosa et al, 2017] and human B cells [Goel et al, 2020]), allowing to avoid or minimize systemic inflammation caused by treatment with type I IFNs (Broggi et al, 2020; Fig. 1).…”

“…Severe lung inflammation and tissue damage are hallmarks of COVID-19, significantly contributing to mortality from this infection (Mehta et al, 2020); thus, enhancement of inflammation and cytokine storm must be avoided. However, it remains to be elucidated whether IFNLR can be up-regulated upon stimulation or in a highly inflamed environment, increasing the risk of possible adverse effects of IFN-λ on human cells (Espinosa et al, 2017;Goel et al, 2020). The absence of pro-inflammatory effects in the lungs (Davidson et al, 2016;Forero et al, 2019;Galani et al, 2017) is one of the most important arguments for the specific advantage of IFN-λ over type I IFNs as a treatment option for COVID-19.…”