Modeling T H 2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma

Immunol Rev. 2017 Jul;278(1):20-40. doi: 10.1111/imr.12549.

Abstract

In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4+ T-helper type-2 lymphocytes (TH 2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical TH 2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of TH 2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote TH 2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of TH 2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches.

Keywords: T-helper cell; allergic inflammation; cytokine; innate immunity; microRNA; steroid resistance.

Publication types

  • Review
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Asthmatic Agents / pharmacology
  • Anti-Asthmatic Agents / therapeutic use
  • Antibodies, Anti-Idiotypic / pharmacology
  • Antibodies, Anti-Idiotypic / therapeutic use
  • Asthma / drug therapy
  • Asthma / etiology*
  • Asthma / metabolism*
  • Asthma / pathology
  • Cell Communication
  • Chemokine CCL11 / metabolism
  • Cytokines / metabolism
  • Cytokines / pharmacology
  • Cytokines / therapeutic use
  • Disease Susceptibility
  • Drug Resistance
  • Humans
  • Immune System / cytology
  • Immune System / immunology
  • Immune System / metabolism
  • Immunoglobulin E / immunology
  • Immunomodulation
  • MicroRNAs / genetics
  • Models, Biological*
  • Respiratory Hypersensitivity / etiology
  • Respiratory Hypersensitivity / metabolism
  • Respiratory Hypersensitivity / pathology
  • Signal Transduction
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism*

Substances

  • Anti-Asthmatic Agents
  • Antibodies, Anti-Idiotypic
  • Chemokine CCL11
  • Cytokines
  • MicroRNAs
  • anti-IgE antibodies
  • Immunoglobulin E