IL-1 family cytokines trigger sterile inflammatory disease

Abstract

Inflammation plays vital roles in protective responses against pathogens and tissue repair, however, improper resolution of inflammatory networks is centrally involved in the pathogenesis of many acute and chronic diseases. Extensive advances have been made in recent years to define the inflammatory processes that are required for pathogen clearance, however, in comparison, less is known about the regulation of inflammation in sterile settings. Over the past decade non-communicable chronic diseases that are potentiated by sterile inflammation have replaced infectious diseases as the major threat to global human health. Thus, improved understanding of the sterile inflammatory process has emerged as one of the most important areas of biomedical investigation during our time. In this review we highlight the central role that interleukin-1 family cytokines play in sterile inflammatory diseases.

Keywords: IL-1; IL-18; IL-33; NLRP3; Sterile inflammation; autoinflammatory disease; caspase-1; inflammasome.

FIGURE 1

Sterile inflammatory diseases. Sterile inflammatory diseases can affect multiple organ systems and are a major threat to global human health.

FIGURE 2

Sterile inflammasome activation. Endogenous, metabolic, and exogenous danger-associated signals activate NLRP3 in the cytosol. Detection of danger signals by NLRP3 promotes the recruitment of ASC and caspase-1 into a multi-protein complex known as the inflammasome. Inflammasome formation provides the necessary molecular platform to promote self-cleavage and activation of caspase-1. Activated caspase-1 cleaves the pro-forms of IL-1β and IL-18, which is required for their secretion and biological activity. Inflammasome-derived IL-1β, and IL-1α that is released from dying cells bind IL-1R, whereas IL-18 has its own receptor. Engagement of IL-1R or IL-18R promotes the robust production of secondary proinflammatory molecules (TNFα, IL-6, KC, etc.) that can then trigger additional immune cell recruitment and activation.

FIGURE 3

Necrotic cells trigger sterile inflammation. Necrotic cells potently induce sterile inflammation through multiple mechanisms. IL-1α that is released from necrotic cells induces the generation of cytokines and chemokines that are associated with granulopoiesis and neutrophil recruitment (G-CSF, KC, IL-6, etc.). In addition, multiple danger-associated molecular pattern molecules (DAMPs) including uric acid, reactive oxygen species (ROS), and ATP are released during necrosis and can promote the expression of factors that are involved in inflammation and neutrophil recruitment.