Current Understanding of Asthma Pathogenesis and Biomarkers

Abstract

Asthma is a heterogeneous lung disease with variable phenotypes (clinical presentations) and distinctive endotypes (mechanisms). Over the last decade, considerable efforts have been made to dissect the cellular and molecular mechanisms of asthma. Aberrant T helper type 2 (Th2) inflammation is the most important pathological process for asthma, which is mediated by Th2 cytokines, such as interleukin (IL)-5, IL-4, and IL-13. Approximately 50% of mild-to-moderate asthma and a large portion of severe asthma is induced by Th2-dependent inflammation. Th2-low asthma can be mediated by non-Th2 cytokines, including IL-17 and tumor necrosis factor-α. There is emerging evidence to demonstrate that inflammation-independent processes also contribute to asthma pathogenesis. Protein kinases, adapter protein, microRNAs, ORMDL3, and gasdermin B are newly identified molecules that drive asthma progression, independent of inflammation. Eosinophils, IgE, fractional exhaled nitric oxide, and periostin are practical biomarkers for Th2-high asthma. Sputum neutrophils are easily used to diagnose Th2-low asthma. Despite progress, more studies are needed to delineate complex endotypes of asthma and to identify new and practical biomarkers for better diagnosis, classification, and treatment.

Keywords: asthma; biomarker; cytokine; inflammation; smooth muscle.

Figure 1

Mechanism of Th2-high asthma. When allergens enter the low airways, dendritic cells (DCs) present the allergens to Th2 cells, which secrete Th2 cytokines, including interleukin (IL)-5, IL-4, and IL-13. IL-4 and IL-13 activate B cells, which produce IgE. IgE subsequently binds to surface of mast cells. When the same allergens enter the airways, they interact with IgE, which induces mast cells to release mediators, such as leukotrienes (LTs), histamine, and ILs. These mediators irritate airway smooth muscle and induce bronchoconstriction. In addition, IL-5 facilitates eosinophil recruitment to the lungs. Eosinophils also release mediators, including major basic protein (MBP), which stimulates mast cells to release histamines and LTs. MBP also inhibits M₂ receptor and promotes acetylcholine release from cholinergic nerves and induces bronchospasm. Furthermore, IL-13 directly sensitizes airway smooth muscle contraction, stimulates epithelial cells to secret mucins, and induces fibrosis. Th9 cells can secrete IL-9, which activates Th2 cells and promotes mast cell accumulation. Lastly, epithelium injury by infection and pollutants induces release of cytokines, including thymic stromal lymphopoietin (TSLP), IL-25, and IL-33, which activate type 2 innate lymphoid cells (ILC2) and produce Th2 cytokines, such as IL-5 and IL-13.

Figure 2

Mechanism of Th2-low asthma. Th17 cytokines: Bacteria promote Th17 cell differentiation via antigen-presenting cells (APCs). Variants in the IL-17 pathway genes also contribute to IL-17 upregulation. IL-17 can stimulate epithelial cells and fibroblasts to release neutrophil chemoattractants CXCL1/5/8 which recruit neutrophils to the lungs. Furthermore, IL-17A enhances airway smooth muscle contraction, migration, and proliferation, which facilitates AHR and airway remodeling, Th1 cytokines: Infection and epithelial injury promote Th1 cell maturation and secrete Th1 cytokines, including TNF-α and IFN-γ. TNF-α synergizes with IL-17 cytokines to promote neutrophil recruitment. Furthermore, TNF-α enhances airway smooth muscle contraction. IFN-γ and TNF-α upregulate Ca²⁺ signaling in airway smooth muscle and induces AHR. In addition, IFN-γ promotes neutrophil recruitment in the presence of IL-17 cytokines.

Figure 3

Emerging mechanisms of asthma. Asthma has long been viewed as an inflammatory disease. However, there is accumulating evidence that inflammation-independent processes also contribute to asthma progression. Genetic variance and epigenetics (e.g., miRs) affect expression of proteins, including kinases, adapter protein, ORMDL3, Gasdermin B, and matrix metalloproteinases in lung tissues, which drive asthma progression.