Advances in non-type 2 severe asthma: from molecular insights to novel treatment strategies

Abstract

Asthma is a prevalent pulmonary disease that affects more than 300 million people worldwide and imposes a substantial economic burden. While medication can effectively control symptoms in some patients, severe asthma attacks, driven by airway inflammation induced by environmental and infectious exposures, continue to be a major cause of asthma-related mortality. Heterogeneous phenotypes of asthma include type 2 (T2) and non-T2 asthma. Non-T2 asthma is often observed in patients with severe and/or steroid-resistant asthma. This review covers the molecular mechanisms, clinical phenotypes, causes and promising treatments of non-T2 severe asthma. Specifically, we discuss the signalling pathways for non-T2 asthma including the activation of inflammasomes, interferon responses and interleukin-17 pathways, and their contributions to the subtypes, progression and severity of non-T2 asthma. Understanding the molecular mechanisms and genetic determinants underlying non-T2 asthma could form the basis for precision medicine in severe asthma treatment.

FIGURE 1

The causes of non-type 2 (T2) asthma. Environmental pollutants (e.g. ozone, particulate matter, diesel exhaust particles and cigarette smoke), pathogen infections (e.g. viral infections, bacterial infections and fungal infections), genetic factors and obesity are major causes of non-T2 asthma.

FIGURE 2

The roles of the inflammasome in asthma development. Upon pathogen infection, inflammasome proteins including nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 1 (NLRP1), NLRP3, NLRC4, NLRP6 and absent in melanoma 2 (AIM2) are induced and recruit apoptosis-associated speck-like protein containing a CARD (ASC) for the activation of caspase-1, which cleaves pro-interleukin (IL)-1β)/pro-IL-18 as well as gasdermin D (GSDMD). The cleaved N-GSDMD mediates pore formation, leading to the release of inflammatory cytokines such as IL-1β and IL-18 to recruit neutrophils and promote inflammation. Subsequently, activated neutrophils release DNA and in turn, activate AIM2 inflammasome in asthmatics. Macrophage migration inhibitory factor (MIF) and obesity promote inflammasome activation. Various pharmacological inhibitors (shown in green), such as ISO-1 for MIF, MCC950 for NLRP3 and Ac-YVAD-cho for caspase-1 can potentially improve neutrophilic asthma.

FIGURE 3

The activation of interferon (IFN) response upon respiratory viral infection. Viral infection may activate two major pathways: the mitochondrial antiviral-signalling protein (MAVS)–TANK binding kinase 1 (TBK1) pathway and the cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway. Upon respiratory virus infection, the viral RNA could be sensed by RNA sensors, including retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated gene 5 (MDA-5). Next, the sensors recruit MAVS, translocating into mitochondria, for the phosphorylation of TBK1. Alternatively, the mitochondrial DNA or other intracellular DNA is recognised by DNA sensor cGAS, resulting in the production of the second messenger 2′3′ cyclic GMP-AMP (cGAMP), activating STING, and subsequent phosphorylation of TBK1. The phosphorylated TBK1 leads to the phosphorylation and activation of IFN regulatory factor 3 (IRF3), which translocates from the cytoplasm to nucleus to mediate type I and type III IFN production. Type I and type III IFN activate the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway by binding to IFN receptors and further amplify the production of IFN-stimulated genes (ISGs).