Allergic Airway Disease Pathogenesis and Treatment

Allergic airway disease encompasses a spectrum of inflammatory disorders characterised by reversible airway obstruction, bronchial hyperresponsiveness and chronic remodelling of the bronchial wall. At its core is a maladaptive immune response to innocuous environmental antigens—typically driven by type 2 T helper (Th2) cell cytokines such as interleukin-4, interleukin-5 and interleukin-13—that orchestrate eosinophilic inflammation, mucus overproduction and smooth muscle contraction. A subset of patients exhibits non‐Th2 phenotypes, in which interleukin-17–producing T cells, neutrophils and inflammasome activation predominate, often correlating with corticosteroid resistance. Structural elements of the airway, including epithelial barrier disruption, altered extracellular matrix and vascular remodelling, further perpetuate disease chronicity. Current management stratifies therapies according to severity: inhaled corticosteroids remain the backbone of anti‐inflammatory control, while targeted biologics against immunoglobulin E, interleukin-5 or the interleukin-4 receptor α subunit have significantly improved outcomes in severe Th2‐high disease. Emerging strategies include modulation of metabolic pathways in immune cells, inhibition of key phosphatases and transferases implicated in steroid-resistant inflammation, and microbiome‐based interventions aimed at restoring airway homeostasis. This integrated approach seeks to address both immune dysregulation and tissue remodelling for long‐term disease control.

Research from Nature Portfolio

Recent studies have identified dual‐specificity phosphatase 2 (DUSP2) as a critical mediator in steroid-resistant neutrophilic asthma. A combination of transcriptome analysis and murine modelling demonstrated that genetic or pharmacological inhibition of DUSP2 attenuates airway neutrophilia and reduces expression of interleukin-17A and tumour necrosis factor-α, suggesting a novel molecular target for refractory disease. In complementary work, myeloid-specific deletion of the small GTPase Rheb1 was shown to skew macrophage polarisation towards an anti-inflammatory M2 phenotype, exacerbating ovalbumin-induced airway hyperresponsiveness and eosinophilic inflammation. This finding underscores the importance of mTORC1 signalling in macrophage function and opens avenues for metabolic reprogramming therapies in allergic airway disease.

Allergic Airway Disease Pathogenesis and Treatment publication trend

The graph below shows the total number of articles in allergic airway disease pathogenesis and treatment across all publications each year (not limited to Nature Index journals).

Technical terms

Th2 cell: A subset of CD4+ T helper cells that produce interleukin-4, interleukin-5 and interleukin-13, driving eosinophilic inflammation and IgE production.

Th17 cell: A subset of CD4+ T helper cells that secrete interleukin-17, promoting neutrophilic inflammation and steroid-resistant airway disease.

Eosinophil: A granulocytic leukocyte involved in type 2 inflammation, releasing cytotoxic granules and cytokines that contribute to airway damage.

Neutrophil: A granulocytic leukocyte implicated in non‐Th2 airway inflammation, often associated with severe, corticosteroid‐insensitive disease.

Airway hyperresponsiveness (AHR): Exaggerated bronchoconstrictive response to stimuli, a hallmark of asthma reflecting airway smooth muscle and inflammatory cell interactions.

Macrophage polarization: The functional programming of macrophages into pro-inflammatory (M1) or anti-inflammatory (M2) states, influencing tissue inflammation and repair.

Inflammasome: A multiprotein complex that activates caspase-1, leading to maturation and release of interleukin-1β and driving innate immune responses.

Oxidative phosphorylation (OXPHOS): A mitochondrial metabolic pathway that generates ATP and influences immune cell fate and function during inflammation.

DUSP2: Dual‐specificity phosphatase 2, an enzyme that dephosphorylates MAP kinases and regulates inflammatory signalling in steroid-resistant asthma.

γ-Glutamyl transferase: An enzyme involved in glutathione metabolism and redox homeostasis, whose inhibition can attenuate airway inflammation.

References

1. The preprogrammed anti-inflammatory phenotypes of CD11chigh macrophages by Streptococcus pneumoniae aminopeptidase N safeguard from allergic asthma. Journal of Translational Medicine (2023).
2. Inhibition of γ-glutamyl transferase suppresses airway hyperresponsiveness and airway inflammation in a mouse model of steroid resistant asthma exacerbation. Frontiers in Immunology (2023).
3. Characterization and inhibition of inflammasome responses in severe and non-severe asthma. Respiratory Research (2023).
4. Bioinformatic analysis and experimental validation of the potential gene in the airway inflammation of steroid-resistant asthma. Scientific Reports (2023).
5. Rheb1 deletion in myeloid cells aggravates OVA-induced allergic inflammation in mice. Scientific Reports (2017).