Negative regulation of type I IFN signaling

Abstract

Type I IFNs (α, β, and others) are a family of cytokines that are produced in physiological conditions as well as in response to the activation of pattern recognition receptors. They are critically important in controlling the host innate and adaptive immune response to viral and some bacterial infections, cancer, and other inflammatory stimuli. However, dysregulation of type I IFN production or response can contribute to immune pathologies termed "interferonopathies", pointing to the importance of balanced activating signals with tightly regulated mechanisms of tuning this signaling. Here, we summarize the recent advances of how type I IFN production and response are controlled at multiple levels of the type I IFN signaling cascade.

Elevated monocyte-specific type I interferon signalling correlates positively with cardiac healing in myocardial infarct patients but interferon alpha application deteriorates myocardial healing in rats

“…[6, 12, 22, 33] Type I IFN activation can either induce inflammation following a viral or bacterial infection, or contain a suppressive role in certain chronic infections [1, 11]. Variability in this response is highly dependent on cell type, pathogens and the environmental context [1]. In rats, we showed that post-MI IFN-α administration altered the distribution of circulating monocyte subsets towards the pro-inflammatory CD43-lo monocyte at day 2 in comparison to placebo, a shift which has generally been associated with an expanded infarcted area [31, 32].…”

“…Type I IFN activation occurs classically through the IFN-α receptor (IFNAR). This induces activation of the Jak–Stat pathway resulting in Stat1 and Stat2 dimerization that initiates nuclear translocation of IFN regulatory transcription factors (IRF) and subsequent transcription of ISGs [1, 7, 23]. King et al demonstrated that MI activates IRF3-dependent signalling through macrophages upon dsDNA sensing at day 4 following MI.…”

“…Exaggerated IFN responses are increasingly associated with human autoimmune diseases and could detrimentally affect the functioning of type I IFN [1]. Also, the concentration and duration of IFN production together with specific timing of action can be crucial for accurate IFN functioning [1, 2].…”

Attenuation of interferon regulatory factor 7 activity in local infectious sites of trachea and lung for preventing the development of acute lung injury caused by influenza A virus

“…As reported, IAV infection can contribute to ALI, 2 which is associated with excessive type I IFN (especially IFN-a) production, 41 and IRF7 is a major transcription factor for the production of IFN-a. 30 We speculated that IRF7 played a key role in local immune responses, and correlated with IAV-induced ALI.…”

Type I interferons and endoplasmic reticulum stress in health and disease

“…Despite this, production of type I IFNs is not specific for non-sterile pathologies. In various sterile pathologies, type I IFNs play either a disease ameliorating (e.g., cancer) or even a disease exacerbating role (e.g., autoimmune diseases especially interferonopathies) (Arimoto et al, 2018;Burdick et al, 2009;Durbin et al, 2000;Palucka et al, 2005;Rizzo et al, 2014). This is made possible by a major overlap (in terms of shared cognate PRRs) between danger signals derived from pathogens (together classified under the term, pathogen-associated molecular patterns or PAMPs) and those of "self" or endogenous origin (together classified under the term, damageassociated molecular patterns or DAMPs); as well as the ubiquitous expression of IFNAR1/2 (de Weerd et al, 2013;Garg and Agostinis, 2017;Garg et al, 2017c;Ragimbeau et al, 2003;Rubartelli and Lotze, 2007).…”