The most studied biological role of type III interferons (IFNs) has so far been their antiviral activity, but their role in autoimmune and inflammatory diseases remains largely unexplored. Here, we show that treatment with IFN-λ2/IL-28A completely halts and reverses the development of collagen-induced arthritis (CIA) and discover cellular and molecular mechanisms of IL-28A antiinflammatory function. We demonstrate that treatment with IL-28A dramatically reduces numbers of proinflammatory IL-17–producing Th17 and γδ T cells in the joints and inguinal lymph nodes, without affecting T cell proliferative responses or levels of anticollagen antibodies. IL-28A exerts its antiinflammatory effect by restricting recruitment of IL-1b–expressing neutrophils, which are important for amplification of inflammation. We identify neutrophils as cells expressing high levels of IFN-λ receptor 1 (IFNLR1)–IL-28 receptor α (IL28RA) and targeted by IL-28A. Our data highlight neutrophils as contributors to the pathogenesis of autoimmune arthritis and present IFN-λs or agonists of IFNLR1–IL28RA as putative new therapeutics for neutrophil-driven inflammation.
IFN-λ1, -λ2, and -λ3 (or IL-29, IL-28A, and IL-28B, respectively) are members of the class II cytokine family evolutionarily related to both IL-10 and type I IFNs (IFN-α/β), and are collectively referred to as type III IFNs. IFN-λ1 (IL-29) is the main cytokine of this family produced in human cells, but it is not expressed in mice, where IL-28A/B play the major role. Despite the use of a distinct receptor complex, IFNLR1–IL28RA activates similar signaling pathways to that of the type I IFN receptor (Kotenko et al., 2003; Sheppard et al., 2003), and the most studied biological role of IFN-λs has so far been their antiviral activity. However, there is evidence to suggest that they may also have pleiotropic immune functions. IFN-λs can induce antiproliferative and antitumor activities (Dumoutier et al., 2004; Brand et al., 2005; Sato et al., 2006; Zitzmann et al., 2006; Abushahba et al., 2010), as well as immunomodulatory effects, such as proliferation of regulatory T cells (Mennechet and Uzé, 2006). IFN-λs have also been shown to down-regulate Th2 cell–mediated inflammation in murine models of allergic airway disease (Koltsida et al., 2011) and oral tolerance in the intestine (He et al., 2011). Despite these first exciting observations, the role of IFN-λs in autoimmune and inflammatory diseases remains largely unexplored.
To address this issue, we examined the potential of IL-28A as an anti–inflammatory therapeutic in the mouse model of arthritis, collagen induced arthritis (CIA), which shares many similarities with human rheumatoid arthritis (RA), including breach of self-tolerance and generation of autoantibodies, as well as excessive production of inflammatory cytokines, i.e., TNF, IL-1, and IL-17 (Asquith et al., 2009). Here, we show that IL-28A appears to specifically target neutrophil function, and thus impacts upon pathology of inflammatory arthritis.