Journal Article

Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages

Startek, Justyna B., Sad, Subash, Joseph, Julie, Shutinoski, Bojan, McComb, Scott, Cessford, Erin, Gamero, Ana M., Mossman, Karen L., Alturki, Norah A.

2014

Overview

Although it has long been known that inflammatory immune responses are associated with death of cells through necrosis, the mechanisms controlling this process are not yet well understood. Recently a type of programmed inflammatory cell death, necroptosis, has been discovered. In this paper we reveal previously unidentified molecular mechanisms that operate to induce this form of cell death. Our results indicate that in order to undergo necroptosis, immune cells must produce and receive signals from the key immune regulator, interferon. Such interferon-dependent necroptosis of immune cells drives acute inflammatory pathology in a mouse model of sepsis. This work highlights the intimate connection between cell death and inflammation, and may lead to new understanding and treatment of inflammatory pathologies. Myeloid cells play a critical role in perpetuating inflammation during various chronic diseases. Recently the death of macrophages through programmed necrosis (necroptosis) has emerged as an important mechanism in inflammation and pathology. We evaluated the mechanisms that lead to the induction of necrotic cell death in macrophages. Our results indicate that type I IFN (IFN-I) signaling is a predominant mechanism of necroptosis, because macrophages deficient in IFN-α receptor type I (IFNAR1) are highly resistant to necroptosis after stimulation with LPS, polyinosinic-polycytidylic acid, TNF-α, or IFN-β in the presence of caspase inhibitors. IFN-I–induced necroptosis occurred through both mechanisms dependent on and independent of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and led to persistent phosphorylation of receptor-interacting protein 3 (Rip3) kinase, which resulted in potent necroptosis. Although various IFN-regulatory factors (IRFs) facilitated the induction of necroptosis in response to IFN−β, IRF-9–STAT1– or -STAT2–deficient macrophages were highly resistant to necroptosis. Our results indicate that IFN-β–induced necroptosis of macrophages proceeds through tonic IFN-stimulated gene factor 3 (ISGF3) signaling, which leads to persistent expression of STAT1, STAT2, and IRF9. Induction of IFNAR1/Rip3–dependent necroptosis also resulted in potent inflammatory pathology in vivo. These results reveal how IFN-I mediates acute inflammation through macrophage necroptosis.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / Apoptosis / Apoptosis - drug effects / Biological Sciences / caspases / Cells / chronic diseases / Enzyme Activation - drug effects / genes / Inflammation / Interferon / Interferon Type I - metabolism / interferon-alpha / interferon-beta / Interferon-Stimulated Gene Factor 3, gamma Subunit - metabolism / Lipopolysaccharides - pharmacology / macrophages / Macrophages - drug effects / Macrophages - metabolism / Macrophages - pathology / Mice / Mice, Inbred C57BL / Models, Biological / Necrosis / Oligopeptides - pharmacology / Pathology / phosphorylation / PNAS Plus / PNAS PLUS: Significance Statements / Poly I-C - pharmacology / polyinosinic-polycytidylic acid / Proteins / Receptor, Interferon alpha-beta - deficiency / Receptor, Interferon alpha-beta - metabolism / Receptor-Interacting Protein Serine-Threonine Kinases - deficiency / Receptor-Interacting Protein Serine-Threonine Kinases - metabolism / Signal transduction / Signal Transduction - drug effects / tumor necrosis factor-alpha / Tumor Necrosis Factor-alpha - pharmacology