IL-18 biology in severe asthma

Abstract

The role of interleukin-18 (IL-18) and inflammasomes in chronic inflammatory airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), has garnered significant attention in recent years. This review aims to provide an overview of the current understanding of IL-18 biology, the associated signaling pathways, and the involvement of inflammasome complexes in airway diseases. We explore the multifaceted role of IL-18 in asthma pathophysiology, including its interactions with other cytokines and contributions to both T2 and non-T2 inflammation. Importantly, emerging evidence highlights IL-18 as a critical player in severe asthma, contributing to chronic airway inflammation, airway hyperresponsiveness (AHR), and mucus impaction. Furthermore, we discuss the emerging evidence of IL-18's involvement in autoimmunity and highlight potential therapeutic targets within the IL-18 and inflammasome pathways in severe asthma patients with evidence of infections and airway autoimmune responses. By synthesizing recent advancements and ongoing research, this review underscores the importance of IL-18 as a potential novel therapeutic target in the treatment of severe asthma and other related conditions.

Keywords: IL-18; asthma; autoimmunity; eosinophilia; inflammasome.

Figure 1

The summary of IL-18 biology and the immune response in association with asthma pathophysiology. IL-18 is activated by caspase-1 and is secreted by both hematopoietic and non-hematopoietic cells. Once activated, IL-18 binds to IL-18R, which is expressed on the surface of T cells, NK cells, neurons, and epithelial cells, triggering downstream inflammatory events. In the Th1 pathway, IL-18, in synergy with IL-12, stimulates Th1 cell development and enhances IFNγ expression. Conversely, in the Th2 pathway, the interaction between IL-18 and IL-2 promotes a Th2 response, which leads to the production of IL-4 and IL-13. This Th2-mediated response increases airway inflammation, hyperresponsiveness, and mucus metaplasia due to IgE production from B cells and heightened IL-13 levels from differentiated cells. Additionally, IL-18 stimulates mast cells and basophils, leading to the release of histamine, IL-4, and IL-13, further promoting a Th2 asthmatic response. IL-18 also induces eosinophils to express CD101 and CD274, transforming IL-5-responsive naive eosinophils into pathogenic eosinophils, contributing to mucus hypersecretion and airway obstruction. IL-18 signaling is regulated by the IL-18 binding protein, which neutralizes IL-18 activity, and inhibitory effects of IL-37, which binds to IL-18α, recruits IL-1R8, and forms a high-affinity complex. This complex inhibits downstream signaling from IL-18 and induces an anti-inflammatory signal via STAT3. Baso, basophil; CD, cluster of differentiation; IFN, interferon; IgE, immunoglobulin E; IL, interleukin; IL-18BP, IL-18 binding protein; MΦ, macrophage; MC, mast cell; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NK, natural killer; NKT, natural killer T-cell; STAT3, signal transducer and activator of transcription 3; Th, T helper cell; TNF, tumor necrosis factor. Created with Biorender.com.

Figure 2

Mechanism of NLRP3 inflammasome activation: the canonical pathway requires two signals: priming and activation. Priming is initiated by the detection of PAMPs and DAMPs, which activate NF-κB by facilitating its translocation into the nucleus via the myddosome complex. This upregulates pro-IL-1β, pro IL-18, and NLRP3 to form the completed NLRP3 inflammasome complex with ASC and pro-Casp-1. Activation of the NLRP3 inflammasome can be triggered by several mechanisms. Phagocytosis of DAMPs can lead to lysosomal damage and the release of cathepsin B. The binding of extracellular ATP to P2X7R, an ATP-gated ion channel, triggers K+ efflux. Additionally, bacterial toxins and viral pore-forming proteins can create cell membrane pores, also leading to K+ efflux. Other mechanisms include Ca2+ influx and mitochondrial dysfunction, which result in the formation of ROS and the secretion of Ox-mtDNA and cardiolipin. Finally, the activation of caspase-1 leads to the conversion of pro-IL-1β and pro-IL-18 into their active forms. Caspase-1 also cleaves GSDMD into N-GSDMD, resulting in pyroptosis. Similar to NLRP3, activation of other airway-relevant inflammasomes, such as NLRP1, NLRC4, and AIM2, also leads to the production of active IL-1β, active IL-18, active GSDMD, and pyroptosis. AIM2, absent in melanoma 2; ASC, apoptosis-associated speck-like protein containing a CARD; ATP, adenosine triphosphate; CARD, caspase recruitment domain; CLC, Charcot-Leyden crystals; DAMPs, damage-associated molecular patterns; DNA, deoxyribonucleic acid; FADD, Fas-associated protein with death domain; FIIND, function-to-find domain; GSDMD, gasdermin D; IL, interleukin; IRAK-1, interleukin-1 receptor-associated kinase 1; LRR, leucine-rich repeat; mtDNA, mitochondrial DNA; MYD88, myeloid differentiation primary response 88; N-GSDMD, N-terminal gasdermin D; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRC4, NOD-like receptor family CARD domain-containing protein 4; NLRP1, NOD-like receptor family pyrin domain-containing protein 1; NLRP3, NOD-like receptor family pyrin domain-containing protein 3; Ox-mtDNA, oxidized mitochondrial DNA; P2X7R, purinergic receptor P2X ligand-gated ion channel 7; PAMPs, pathogen-associated molecular patterns; PYD, pyrin domain; ROS, reactive oxygen species; TLR, toll-like receptor; TRIF, TIR-domain-containing adapter-inducing interferon-β. Created with Biorender.com.