New targets for type 2-low asthma

Abstract

Asthma is characterized by airway obstruction and inflammation, and presents significant diagnostic and treatment challenges. The concept of endotypes has improved understanding of the mechanisms of asthma and has stimulated the development of effective treatment strategies. Sputum profiles may be used to classify asthma into two major inflammatory types: type 2-high (T2H) and type 2-low (T2L) asthma. T2H, characterized by elevated type 2 inflammation, has been extensively studied and several effective biologic treatments have been developed. However, managing T2L is more difficult due to the lack of reliable biomarkers for accurate diagnosis and classification. Additionally, conventional anti-inflammatory therapy does not completely control the symptoms of T2L; therefore, further research is needed to identify effective biologic treatments. This review provides new insights into the clinical characteristics and underlying mechanisms of severe T2L and investigates potential therapeutic approaches to control the disease.

Keywords: Asthma; Biomarker; Mechanism; Neutrophil; Therapeutics.

Figure 1

Mechanisms of airway inflammation and remodeling in T2L. Following exposure to various environmental triggers, such as viruses, bacteria, smoking, pollutants, and allergens, airway epithelial cells are activated and release the alarmins TSLP and IL-33, as well as IL-8. These cytokines mediate the migration and activation of neutrophils. In addition, increased levels of IFN-γ lead to macrophage activation and polarization, which stimulate neutrophilic airway inflammation. Activated macrophages and dendritic cells release the cytokines IL-6, IL-1β, and IL-23, which mediate differentiation of T_h cells into T_h17 and ILCs into ILC3. This results in the overproduction of IL-17, which in turn promotes airway remodeling by stimulating airway smooth muscle cell hyperplasia, tissue hypertrophy, and the release of IL-8 and TNF-α, thereby activating neutrophils. Furthermore, overproduction of TGF-β1 induces fibroblast proliferation, contributing to airway remodeling in T2L. Images were created using Servier Medical Art software (https://smart.servier.com/), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/). ASM, airway smooth muscle; CXCR2, C-X-C motif chemokine receptor 2; DCs, dendritic cells; IL, interleukin; ILCs, innate lymphoid cells; IFN, interferon; IL-33R, IL-33 receptor; Mϕ, macrophages; Neu, neutrophils; T2L, type 2-low; TGF, transforming growth factor; T_h, T helper; TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoietin.