Comment on: Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus. Rishi R Goel, Xinghao Wang, Liam J O’Neil et al. Proc Natl Acad Sci U S A. 2020 Mar 10;117(10):5409-5419. doi: 10.1073/pnas.1916897117.
Commented by: Maria G. Tektonidou, First Department of Propaedeutic Internal Medicine, Laiko Hospital, Medical School, National and Kapodistrian University of Athens, Greece.
Advances in understanding the genetic and molecular basis of innate immunity have led to identification of type-I Interferon (IFN) as a central mediator in the pathogenesis of SLE (1). Recently, the type III interferon group of anti-viral cytokines (IFNλs), consisted of four IFN-λ (lambda) molecules namely IFN-λ1, IFN-λ2, IFN-λ3 and IFN-λ4, have been recognized as potential key contributors in the immune responses and tissue-specific pathology in SLE (2). IFNλs have been expressed in SLE renal tubule epithelial cells and high circulating levels have been associated with distinct clinical features of active SLE (3, 4). They exert their function through a heterodimeric receptor complex consisted of IFN-receptor 1 (IFNLR1) and IL-10 receptor 2 (IL-10R2). Compared to type-I IFN, they also utilize the JAK/STAT pathway to induce transcription of IFN-stimulated genes. but in in contrast to type I IFN receptor (IFNAR), the IFNLR1 is not invariably expressed in all cell types but mainly on epithelial cells.
In this study, Goel et al, examine the role of IFNλs in immune dysregulation and tissue inflammation in a model of TLR-induced lupus. They showed that wild type (WT) mice treated with Imiquimod, a TLR-7 agonist, developed an autoimmune phenotype consistent with lupus, including increased type I IFN signature, leukocyte activation, specific autoantibodies, and other tissue pathologies in the skin, kidneys, and vasculature. In contrast to the WT mice treated with Imiquimod (which developed a SLE-like phenotype), the Ifnlr1 knock out animals Ifnlr1 (-/-) displayed a healthier phenotype with less splenomegaly and higher number of platelets and hemoglobin. Furthermore, assessing the functionality of the mice model, it was also shown that IFN-λ induced IRF7 expression in WT, but not in Ifnlr1−/− cells. Immunophenotyping these animals, marked differences were seen between WT and Ifnlr1−/− animals in the populations of T- and myeloid cells but not in B-cells. On the other hand, it was observed that immune cells expressed IFNLR1 at very low levels. Also, isolating sub-populations of immune cells, only specific subsets of immune cells have expressed IFN-stimulated genes in response to IFNλ. It was thus hypothesized that IFNλ might be a moderator of the immune response at a local level rather than an activator of immune cells. Indeed, Ifnlr1−/− mice treated with Imiquimod had significantly lower skin inflammation and skin cytokine/chemokine expression compared to WT mice. Furthermore, performing transwell migration assays, keratinocytes treated with IFN-λ produced chemokines mediating migration of monocytes, B-cells and T-cells and promoting inflammation in the skin and kidneys. Finally, IFN-stimulated genes (ISG) expression was higher in kidneys from WT-imiquimod-treated compared to Ifnlr1 (-/-) mice. Similar to keratinocytes, Mesangial cells treated with IFN-λ or IFN-α significantly up-regulated ISGs and chemokine genes CXCL9, CXCL10, and CXCL11. In contrast, no improvement was seen for Ifnlr1−/− mice as regards to the vascular dysfunction of WT-Imiquimod-treated mice.
This study showed that IFNλs have nonredundant functions in TLR7-associated lupus inflammation and that can be important players in lupus immunobiology and tissue specific pathology in SLE. IFN-λ was increased in murine lupus, and Ifnlr1 deficiency reduced immune cell activation and skin and kidney damage without effects on autoantibody production. As the authors highlight, these results need to be replicated in other lupus models also. The role of IFNλ, might also shed some more light in the treatment effects of JAK-inhibitors in SLE.
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