Type I IFN-mediated regulation of IL-1 production in inflammatory disorders

Abstract

Although contributing to inflammatory responses and to the development of certain autoimmune pathologies, type I interferons (IFNs) are used for the treatment of viral, malignant, and even inflammatory diseases. Interleukin-1 (IL-1) is a strongly pyrogenic cytokine and its importance in the development of several inflammatory diseases is clearly established. While the therapeutic use of IL-1 blocking agents is particularly successful in the treatment of innate-driven inflammatory disorders, IFN treatment has mostly been appreciated in the management of multiple sclerosis. Interestingly, type I IFNs exert multifaceted immunomodulatory effects, including the reduction of IL-1 production, an outcome that could contribute to its efficacy in the treatment of inflammatory diseases. In this review, we summarize the current knowledge on IL-1 and IFN effects in different inflammatory disorders, the influence of IFNs on IL-1 production, and discuss possible therapeutic avenues based on these observations.

Fig. 1

The production of bioactive IL-1. Pattern recognition receptor engagement enhances NLRP3 expression and induces IL-1α and pro-IL-1β. Upon sensing specific inflammasome-activating stimuli, NLRP3 assembles into and recruits ASC and procaspase-1 to the inflammasome complex. This multi-protein platform leads to the activation of caspase-1, which proteolytically converts pro-IL-1β into bioactive IL-1β. In contrast, pro-IL-1α does not require cleavage for its activity. The release of both cytokines triggers NF-κB signaling by binding to IL-1R

Fig. 2

Induction and effects of type I IFNs. a The best characterized mechanisms leading to type I IFN induction are initiated by cytoplasmic RLRs and transmembrane TLRs. Signaling pathways activated by these receptors converge in the phosphorylation of IRFs, which translocate into the nucleus and activate the transcription of type I IFN genes. b Type I IFNs signal through a dimeric receptor and activate JAK1 and TYK2. In turn, these kinases phosphorylate STAT1 and STAT2, enabling recruitment of IRF9 to the so-called ISGF3 complex. This trimeric complex binds to ISREs, thereby modulating the expression of ISGs exerting antiviral, immunomodulatory, proapoptotic, and anti-inflammatory functions

Fig. 3

Type I IFNs inhibit IL-1 production. Type I IFN signaling suppresses caspase-1-dependent IL-1β maturation by a STAT1-dependent mechanism, which might involve de novo transcription of a target protein. In addition, type I IFNs induce the expression of IL-1Ra, the natural IL-1R antagonist, and the anti-inflammatory cytokine IL-10. In murine macrophages, enhancement of IL-10 production by type I IFNs also requires the transcription factor STAT1. Interleukin-10, in turn, contributes to the induction of IL-1Ra and to the decrease of pro-IL-1 levels in a STAT3-dependent manner