IL5RA

Detailed Information

Interleukin-5 (IL-5) is a pleiotropic cytokine, also known as T cell-replacing factor, eosinophil colony-stimulating factor 1, and eosinophil differentiation factor. IL-5 is primarily produced by T cells and serves as the principal cytokine regulating the growth, differentiation, recruitment, activation, and survival of eosinophils. Based on structural homology, interleukins can be classified into several protein families, such as the IL-1, IL-2, IL-6, IL-10, and chemokine families. However, IL-5 does not belong to any of these families.

IL-5 is considered a key driver of the Th2 immune pathway and plays a central role in the pathophysiology of eosinophilic asthma. As a potent eosinophilic cytokine, IL-5 is critically involved in various processes, including eosinophil maturation, activation, proliferation, and survival, making it an important therapeutic target for eosinophilic asthma.

Structure and Expression of the IL-5 Receptor

The IL-5 receptor (IL-5R) is a heterodimer composed of a specific IL-5Rα subunit and a non-specific common β-chain (βc). IL-5Rα is the IL-5-specific subunit that binds IL-5 to form a functional heterodimeric receptor complex. The complete receptor consists of a ligand-specific α-chain and a signal-transducing β-chain shared with receptors for IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF or CSF2).

IL-5Rα is highly expressed on the surface of eosinophils and plays a key role in clearing allergens from blood and tissues via eosinophilic responses. Gene Ontology (GO) annotations indicate that the IL5RA gene is associated with cytokine receptor activity and IL-5 receptor activity. CSF3R is an important paralog of IL5RA.

IL-5/IL-5R Signaling Pathway and Molecular Mechanisms

In the presence of IL-5, it binds to the highly expressed IL-5Rα on eosinophil surfaces, subsequently recruiting the βc subunit and forming the IL-5/IL-5Rα/βc complex. Binding of IL-5 to the α subunit induces the assembly of a heterodimeric receptor complex consisting of α and βc subunits. This interaction is dependent on the β subunit, which becomes activated upon ligand binding and is essential for IL-5's biological activity.

Under unstimulated conditions, IL-5Rα constitutively interacts with JAK2. Upon receptor activation, JAK2 becomes stimulated, triggering the JAK-STAT signaling pathway. Additionally, IL-5Rα has been found to interact with syntenin, a syndecan-binding protein necessary for IL-5-mediated activation of the transcription factor SOX4.

Downstream Pathways and Mechanisms of Action

Activation of the IL-5/IL-5R signaling axis leads to stimulation of several downstream pathways, including:

1. JAK/STAT pathway: Primarily mediates gene transcription involved in eosinophil differentiation, proliferation, and survival.
2. MAPK pathway: Regulates cell proliferation and activation.
3. PI3K pathway: Involved in cell survival and chemotaxis.
4. NF-κB pathway: Participates in inflammatory responses and cell survival.

These signaling pathways collectively regulate key eosinophilic functions such as differentiation, degranulation, survival, proliferation, chemotaxis, and adhesion. IL-5R-associated pathways also include MAPK cascade signaling and IL-2 family signaling pathways.

Figure 1. Biological functions of IL-5 in regulating eosinophil activity. (Pelaia C, et al., 2019)

Role of IL-5/IL-5R in Disease

Asthma is a chronic respiratory disorder characterized by recurrent symptoms such as wheezing, coughing, and chest tightness. Eosinophils are among the key inflammatory cells involved in asthma and are pivotal in both allergic and non-allergic asthma subtypes.

Studies show that many patients with severe asthma exhibit a T2-high phenotype characterized by eosinophilic inflammation, marked by eosinophil accumulation in the airways, where they release cytokines, chemokines, and cytotoxic proteins to activate pro-inflammatory pathways. IL-5, being a primary cytokine influencing eosinophil biology, plays a critical role in the pathophysiology of eosinophilic asthma.

Other IL-5/IL-5R-Related Disorders

Beyond asthma, IL-5/IL-5R signaling is implicated in a variety of eosinophil-associated diseases, including:

1. Eosinophilic Granulomatosis with Polyangiitis (EGPA): A vasculitis marked by abnormally elevated eosinophils.
2. Hypereosinophilic Syndrome (HES): Characterized by persistent eosinophilia in blood and tissues.
3. Nasal Polyposis: A nasal disorder linked to eosinophilic inflammation.
4. Eosinophilic Esophagitis: A chronic inflammatory condition of the esophagus with eosinophilic infiltration.
5. Chronic Obstructive Pulmonary Disease (COPD): Some patients exhibit elevated eosinophil levels.

Therapeutic Strategies Targeting IL-5/IL-5R

Three monoclonal antibodies have been approved for clinical use in asthma treatment by targeting the pathogenic IL-5/IL-5R-eosinophil axis:

1. Mepolizumab: A selective IL-5 inhibitor that specifically binds to IL-5 and prevents its interaction with IL-5Rα on eosinophils, thereby reducing eosinophil numbers and activation. It was the first IL-5-targeting monoclonal antibody approved by the FDA in November 2015 and is also indicated for treating EGPA.
2. Reslizumab: Another selective IL-5 inhibitor similar to mepolizumab, it binds specifically to IL-5 to block its receptor interaction. However, it requires intravenous infusion over 20–50 minutes, which is less convenient.
3. Benralizumab: An IL-5Rα antagonist that not only blocks the binding of IL-5 to its receptor but also induces rapid and direct eosinophil depletion from bone marrow, blood, and tissues through antibody-dependent cell-mediated cytotoxicity (ADCC). It is administered once every 8 weeks and offers a faster onset of action with certain clinical advantages.

These three FDA-approved IL-5/IL-5Rα monoclonal antibodies are primarily used to treat eosinophilic asthma. Clinical data have demonstrated that these therapies significantly reduce eosinophil counts, decrease the frequency of asthma exacerbations, and improve lung function.

Recent studies suggest that these antibody therapies also show therapeutic potential in various eosinophil-driven diseases beyond asthma. For instance, Mepolizumab has been approved for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA), and all three drugs are being investigated for other conditions such as hypereosinophilic syndrome (HES), eosinophilic esophagitis, and nasal polyposis.

Compared to traditional corticosteroid therapy, IL-5/IL-5Rα-targeted therapies offer a more precise mechanism of action with fewer systemic side effects, making them particularly suitable for patients with steroid-resistant or steroid-dependent eosinophilic inflammation. Benralizumab, with its ability to induce antibody-dependent cellular cytotoxicity (ADCC), provides rapid and sustained eosinophil depletion and has demonstrated superior effects in certain clinical endpoints, including reduction in oral corticosteroid use and improvements in quality of life metrics.