Cytokine Mediated Type 2 Immune Responses in Airway Inflammation

Type 2 immunity in the airways is orchestrated by specialised cytokines that link epithelial damage to downstream effector networks. Following allergen or pathogen‐induced injury, epithelial cells release ‘alarmins’ such as interleukin-25 (IL-25), interleukin-33 and thymic stromal lymphopoietin. These drivers engage both innate lymphoid cells type 2 (ILC2s) and T helper 2 (Th2) lymphocytes, promoting the secretion of interleukins 4, 5, 9 and 13. The resulting milieu fosters eosinophil recruitment, goblet cell hyperplasia and airway hyperresponsiveness, hallmarks of conditions such as asthma and chronic rhinosinusitis. Cross‐talk with macrophages and dendritic cells further amplifies the response, while receptor complexes formed by IL-17RA/IL-17RB and other family members determine signal strength and duration. Imbalances in this network underpin diverse endotypes, from eosinophilic to neutrophilic asthma, and inform the selection of targeted biologics. Advances in structural and mechanistic studies are refining our understanding of cytokine–receptor interactions, paving the way for precision therapies that intercept type 2 pathways at multiple levels.

Research from Nature Portfolio

In‐depth structural studies have delineated how IL-25 engages its receptor subunits to trigger type 2 programmes. Cryo‐electron microscopy has revealed a C2-symmetric assembly in which an IL-25 homodimer bound to IL-17RB is flanked by two IL-17RA co-receptors via a ‘tip-to-tip’ interface. This architecture imposes spatial constraints on intracellular domains, ensuring selective recruitment of downstream adaptors and kinases. Insights into receptor–receptor allostery and the distinct conformations of binary versus ternary complexes offer a blueprint for rational design of antagonists that disrupt key contact sites without compromising related pathways.

Cytokine Mediated Type 2 Immune Responses in Airway Inflammation publication trend

The graph below shows the total number of articles in cytokine mediated type 2 immune responses in airway inflammation across all publications each year (not limited to Nature Index journals).

Technical terms

Alarmin: Epithelial-derived cytokine released upon damage that activates innate and adaptive immunity.

ILC2: Group 2 innate lymphoid cell that responds to IL-25, IL-33 and TSLP by producing type 2 cytokines.

Th2 cell: Subset of CD4+ T helper lymphocytes that secrete IL-4, IL-5 and IL-13 to drive type 2 inflammation.

Tip-to-tip interface: Structural contact between receptor ectodomains critical for signal transduction initiation.

M1/M2 macrophage polarisation: Functional states of macrophages, where M1 is pro-inflammatory and M2 is associated with tissue repair and type 2 immunity.

References

1. New insights into the function of Interleukin-25 in disease pathogenesis. Biomarker Research (2023).
2. Evaluation of the safety, tolerability, pharmacokinetics and pharmacodynamics of SM17 in healthy volunteers: results from pre-clinical models and a first-in-human, randomized, double blinded clinical trial. Frontiers in Immunology (2024).
3. Exogenous IL-25 ameliorates airway neutrophilia via suppressing macrophage M1 polarization and the expression of IL-12 and IL-23 in asthma. Respiratory Research (2023).
4. Organizing structural principles of the IL-17 ligand–receptor axis. Nature (2022).