The Role of Interferons in Inflammation and Inflammasome Activation

Abstract

Inflammation is an essential physiological process, which enables survival during infection and maintains tissue homeostasis. Interferons (IFNs) and pro- and anti-inflammatory cytokines are crucial for appropriate response to pathogens, damaged cells, or irritants in inflammatory response. The inflammasom is multiprotein complex, which initiates cleavage of pro-inflammatory cytokines IL-1β and IL-18 into active forms. In addition, inflammasomes initiate pyroptotic cell death. In the present review, I summarize and analyze recent findings regarding the cross talk of IFNs and inflammasomes.

Keywords: caspase-1; caspase-11; cyclic GMP-AMP synthase; guanylate-binding protein; inflammasome; interferon; macrophages; pyropotosis.

Figure 1

Type I interferons (IFNs) and inflammasome activation. Initial pathogen-associated molecular patterns (PAMPs) recognition by pattern recognition receptors induces IFN-β expression. IFNs could signal in an autocrine or paracrine manner and trigger expression of IFN-stimulated genes (ISGs): interferon regulatory factor (IRF)1, AIM2, caspase-11. Caspase-11 recognizes cytosolic LPS and induces IL-1β processing in an Nlrp3-dependent manner and triggers pyroptosis through gasdermin D (GSDMD) cleavage. Active caspase-1 and caspase-11 cleave GSDMD and the released gasdermin-N domain binds to phosphoinositides in the plasma membrane, oligomerizes to generate membrane pores, and initiates cell death-pyroptosis. IRF induce the expression of guanylate-binding proteins (GBPs), which target vacuolar and cytosolic bacteria, compromise the integrity of bacterial cells, and expose PAMPs like LPS and dsDNA to cytosolic sensors, caspase-11, and AIM2. IFN signaling triggers the expression of inducible nitric oxide synthase (iNOS), which upregulates cellular nitric oxide (NO) levels leading to NLRP3 S-nitrosylation.

Figure 2

Interferon (IFN) signaling influence recognition of intracellular pathogens—cytosolic bacteria and influenza A virus (IAV). IFNs signaling trigger the transcription factor interferon regulatory factor (IRF)1, which promotes expression of guanylate-binding proteins (GBPs) and interferon response gene B10 (IRGB10). IRGB10, together with GBPs permeabilizes the membrane of Gram-negative bacteria, an action that results in release of bacterial DNA and LPS. Bacterial cytosolic DNA is sensed by Aim2 inflammasome and LPS directly interacts with caspase-11. Type I IFN signaling mediates upregulation of interferon-inducible protein Z-DNA-binding protein 1 (ZBP1), which recognizes the IAV proteins and triggers NLRP3 inflammasome activation, as well as induction of apoptosis, necroptosis, and pyroptosis in IAV-infected cells.