Innate lymphoid cells in asthma: Will they take your breath away?

Abstract

Asthma is a complex and heterogeneous disease that is characterized by airway hyper-reactivity (AHR) and airway inflammation. Although asthma was long thought to be driven by allergen-reactive TH 2 cells, it has recently become clear that the pathogenesis of asthma is more complicated and associated with multiple pathways and cell types. A very exciting recent development was the discovery of innate lymphoid cells (ILCs) as key players in the pathogenesis of asthma. ILCs do not express antigen receptors but react promptly to "danger signals" from inflamed tissue and produce an array of cytokines that direct the ensuing immune response. The roles of ILCs may differ in distinct asthma phenotypes. ILC2s may be critical for initiation of adaptive immune responses in inhaled allergen-driven AHR, but may also function independently of adaptive immunity, mediating influenza-induced AHR. ILC2s also contribute to resolution of lung inflammation through their production of amphiregulin. Obesity-induced asthma is associated with expansion of IL-17A-producing ILC3s in the lungs. Furthermore, ILCs may also contribute to steroid-resistant asthma. Although the precise roles of ILCs in different types of asthma are still under investigation, it is clear that inhibition of ILC function represents a potential target that could provide novel treatments for asthma.

Keywords: Airway hyper-reactivity; Allergy; Asthma; Influenza; Innate lymphoid cells; Obesity.

Figure 1. Asthma phenotypes and related immune cell types

Asthma is a heterogeneous disease with multiple phenotypes associated with different cell types and cytokines. The Type 2^high phenotype is associated with Type 2 cytokines and activation of T_H2 cells. This phenotype is often correlated with eosinophilia and activation of DCs, as well as ILC2s. In the Type 2^low phenotype observed in some asthmatics, lower levels of T_H2 cytokines and fewer eosinophils are detected. Type 2 cytokine inhibitors could be promising therapeutic targets for these phenotypes. Although Type 2 inflammation is important for asthma development, steroid-resistant and obesity-associated asthma phenotypes are often associated with non-Type 2 inflammatory responses. ILC2s, ILC3s and T2M (type 2 myeloid cells) have been associated with steroid-resistant asthma. M1 macrophages, ILC3s, and neutrophils induce inflammation to worsen obesity-related asthma. Further understanding of these diverse asthma phenotypes may lead to new therapies.

Figure 2. Two faces of ILC2 cells: pathogenic and protective functions in asthma

(A)In response to allergen, helminth or viral infection, or sensed “danger” signals, airway epithelial cells release innate cytokines, particularly interleukin-25 (IL-25), interleukin-33 (IL-33), and thymic stromal lymphopoeitin (TSLP), which activate ILC2s and initiate an inflammatory cascade leading to lung inflammation and hyperreactivity. Activated ILC2s produce Type 2 cytokines such as IL-4, IL-5, IL-9 and IL-13. IL-4 subsequently stimulates Th2 cells, IL-5 induces eosinophilic inflammation, IL-9 induces airway hypersensitivity and IL-13 causes airway hypersensitivity as well as activation of M2 macrophages. ILC2s also produce arginase-1 which stimulates M2 macrophages. NKT cells directly interact with macrophages, inducing further IL-33 production to stimulate ILC2s. (B) In contrast, ILCs also participate in lung and metabolic homeostasis. ILC2s produce amphiregulin, which promotes repair of the airway epithelium. ILC2s and NKT cells sustain eosinophils and M2 macrophages by secretion of type 2 cytokines including IL-5 and IL-13, and promote beige fat biogenesis. The ILC2-eosinophil axis protects from metabolic dysregulation and protects against obesity-associated asthma.