New perspectives on the regulation of type II inflammation in asthma

Abstract

Asthma is a chronic inflammatory disease of the lungs which has been thought to arise as a result of inappropriately directed T helper type-2 (Th2) immune responses of the lungs to otherwise innocuous inhaled antigens. Current asthma therapeutics are directed towards the amelioration of downstream consequences of type-2 immune responses (i.e. β-agonists) or broad-spectrum immunosuppression (i.e. corticosteroids). However, few approaches to date have been focused on the primary prevention of immune deviation. Advances in molecular phenotyping reveal heterogeneity within the asthmatic population with multiple endotypes whose varying expression depends on the interplay between numerous environmental factors and the inheritance of a broad range of susceptibility genes. The most common endotype is one described as "type-2-high" (i.e. high levels of interleukin [IL]-13, eosinophilia, and periostin). The identification of multiple endotypes has provided a potential explanation for the observations that therapies directed at typical Th2 cytokines (IL-4, IL-5, and IL-13) and their receptors have often fallen short when they were tested in a diverse group of asthmatic patients without first stratifying based on disease endotype or severity. However, despite the incorporation of endotype-dependent stratification schemes into clinical trial designs, variation in drug responses are still apparent, suggesting that additional genetic/environmental factors may be contributing to the diversity in drug efficacy. Herein, we will review recent advances in our understanding of the complex pathways involved in the initiation and regulation of type-2-mediated immune responses and their modulation by host factors (genetics, metabolic status, and the microbiome). Particular consideration will be given to how this knowledge could pave the way for further refinement of disease endotypes and/or the development of novel therapeutic strategies for the treatment of asthma .

Keywords: Th2 inflammation; alarmins; allergic inflammation; asthma; cellular metabolism; cytokines; signalling.

Figure 1.. Summary of the canonical Th2 pathway and “new spins” on the pathways that lead to allergic inflammation.

Newly appreciated modifiers of Th2 inflammation, such as alarmins, environmental factors, and G-protein-coupled receptor pathways, are indicated and discussed further in the text. Question marks indicate that the role of these new players is not completely clear or that they have been reported to have an enhancing or reducing effect on the outcome measure depending on the publication. AKT, protein kinase B; cAMP, cyclic adenosine monophosphate; DENND1B, DENN domain-containing 1B; FIZZ1, found in inflammatory zone 1; GRB10, growth factor receptor bound protein 10; IL, interleukin; IL-13Rα1, interleukin-13 receptor α1; ILC2, type-2 innate lymphoid cells; IRS-2, insulin receptor substrate 2; mTORC, mammalian target of rapamycin complex; PI3-K, phosphoinositide 3-kinase; SNP, single nucleotide polymorphism; SOCS, suppressor of cytokine signaling; STAT6, signal transducer and activator of transcription 6; STUB1, STIPI homology and U-box-containing protein 1; TAS2R, taste 2 receptor; TGF-β, transforming growth factor-β; TH2, T helper type-2; TSLP, thymic stromal lymphopoietin; YKL-40, chitinase-3-like protein 1.