IL5RA -interleukin 5 receptor subunit alpha | Elisa - Clia - Antibody - Protein

Background

Interleukin-5 receptor subunit alpha (IL5RA) is a protein critical for mediating immune responses involving eosinophils. Encoded by the IL5RA gene, this receptor forms a part of the IL-5 receptor complex, which is primarily responsible for binding interleukin-5 (IL-5), a cytokine crucial in regulating the growth, differentiation, and activation of eosinophils and basophils. Eosinophils, in particular, are involved in immune responses against parasitic infections and play a role in allergic inflammation and diseases such as asthma and eosinophilic esophagitis.

IL-5, along with its receptor IL5RA, is also implicated in the development and maintenance of T-helper 2 (Th2)-mediated immune responses, which play a role in allergic diseases. By engaging IL5RA on eosinophils and other cells, IL-5 signaling promotes survival, activation, and accumulation of these cells at inflammatory sites. Due to its central role in driving eosinophil-mediated inflammation, IL5RA is a target for therapeutic interventions, especially in asthma, chronic rhinosinusitis with nasal polyps, and hypereosinophilic syndrome.

Protein Structure

IL5RA is a type I transmembrane protein with distinct structural domains tailored for ligand binding, signal transduction, and cellular activation. The structural composition of IL5RA includes:

Extracellular Domain (ECD):

• The ECD consists of approximately 320 amino acids and is essential for binding IL-5. This domain contains two fibronectin type III (FNIII)-like domains, which contribute to its interaction with IL-5. The cytokine-binding homology region (CHR) within the ECD contains a “WSXWS” motif, which is common among type I cytokine receptors and is essential for maintaining structural stability and enabling IL-5 binding.
• The ECD also possesses multiple conserved cysteine residues that form disulfide bonds, enhancing the stability and correct folding of the receptor. Additionally, N-linked glycosylation sites are present in the ECD, further stabilizing the receptor and optimizing ligand binding.

Transmembrane Domain (TMD):

• The TMD consists of a single alpha-helical segment that anchors IL5RA to the cell membrane. This domain plays a role in receptor dimerization, facilitating the formation of the IL-5 receptor complex with beta subunits (CSF2RB), which are required for signal transduction. The TMD is integral in stabilizing the receptor complex and ensuring proper orientation on the cell surface.

Intracellular Domain (ICD):

• The ICD of IL5RA is relatively short and lacks intrinsic enzymatic activity. Instead, it recruits signaling molecules to propagate downstream signals. The ICD contains sites for phosphorylation, which are critical for activating intracellular signaling pathways upon IL-5 binding. When phosphorylated, the ICD serves as a docking site for Janus kinase 2 (JAK2) and other signaling proteins, initiating cascades that drive cellular activation, survival, and differentiation.

Classification and Subtypes

IL5RA belongs to the type I cytokine receptor family, specifically the hematopoietin receptor superfamily. This family includes receptors that bind to various cytokines involved in hematopoiesis, immune regulation, and inflammatory responses. IL5RA does not have subtypes, but it requires association with the common beta chain (βc or CSF2RB) to form a functional IL-5 receptor complex. This beta subunit is shared among the receptors for IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). The interaction of IL5RA with the common beta subunit differentiates it from other cytokine receptors and defines its unique signaling capacity.

Function and Biological Significance

The primary function of IL5RA is to mediate responses to IL-5, a cytokine specifically involved in the regulation of eosinophils and, to a lesser extent, basophils. Key functions and biological roles of IL5RA include:

Eosinophil Differentiation and Survival:

• IL5RA signaling drives the differentiation of eosinophil precursors in the bone marrow, promoting their maturation and survival. Upon binding IL-5, IL5RA activates JAK2, leading to downstream phosphorylation of STAT proteins (particularly STAT5), which are critical for eosinophil survival and anti-apoptotic functions. This pathway enables eosinophils to survive longer in the peripheral blood and at sites of inflammation.

Activation and Migration of Eosinophils:

• IL5RA activation enhances the migration and recruitment of eosinophils to inflamed tissues, particularly during allergic responses. IL-5 signaling through IL5RA upregulates adhesion molecules and chemokine receptors on eosinophils, facilitating their accumulation at inflammatory sites. This response is a key component of allergic inflammation in conditions such as asthma and eosinophilic esophagitis.

Role in Th2-Mediated Immune Responses:

• IL5RA and IL-5 are important components of Th2 immunity, a response that counters parasitic infections and promotes allergic reactions. In Th2-dominant conditions, IL5RA contributes to the proliferation of eosinophils, which release inflammatory mediators, cytokines, and cytotoxic granules that can damage pathogens but also cause tissue injury in allergic diseases.

Synergistic Effects with Other Cytokine Receptors:

• The shared beta chain (CSF2RB) in the IL-5 receptor complex allows for coordinated responses with other cytokines, such as GM-CSF and IL-3. This synergy enhances the activation and function of eosinophils and other granulocytes, amplifying the inflammatory response in immune and allergic conditions.

Clinical Issues

Due to its specific role in eosinophil biology, IL5RA is implicated in a range of eosinophilic and allergic disorders:

Asthma:

• IL5RA is a major target in treating eosinophilic asthma, a subtype characterized by elevated eosinophil levels. High IL-5 signaling through IL5RA leads to eosinophil accumulation in the lungs, where these cells release toxic proteins and cytokines that exacerbate inflammation, mucus production, and airway hyperresponsiveness. Mepolizumab and benralizumab, monoclonal antibodies targeting IL-5 and IL5RA, respectively, have been effective in reducing asthma exacerbations by depleting eosinophils.

Eosinophilic Esophagitis:

• IL5RA is involved in eosinophilic esophagitis (EoE), an inflammatory condition of the esophagus with high eosinophil infiltration. IL5RA-targeting therapies have been studied in EoE to alleviate symptoms by reducing eosinophil numbers and inflammation in the esophageal lining.

Hypereosinophilic Syndrome (HES):

• HES is a disorder characterized by persistent eosinophilia and multi-organ involvement. Excessive IL5RA signaling contributes to the high eosinophil counts observed in HES. Anti-IL5RA therapies have shown promise in reducing eosinophil levels and controlling symptoms associated with HES.

Chronic Rhinosinusitis with Nasal Polyps (CRSwNP):

• In CRSwNP, chronic inflammation with eosinophil infiltration leads to the growth of nasal polyps. IL5RA expression on eosinophils contributes to the inflammatory process, making it a therapeutic target in patients with eosinophilic CRSwNP.

Summary

IL5RA plays a vital role in eosinophil biology and Th2-mediated immune responses. Structurally, IL5RA is a type I transmembrane protein with an extracellular domain for IL-5 binding, a transmembrane region for anchoring, and a short intracellular domain that recruits JAK2 and other signaling proteins. The receptor forms a functional complex with the common beta chain (CSF2RB), allowing IL-5 signaling to proceed and activate downstream pathways that enhance eosinophil survival, proliferation, and migration.

In allergic and eosinophilic diseases, such as asthma, eosinophilic esophagitis, and hypereosinophilic syndrome, IL5RA is a key mediator of disease pathogenesis. Therapies targeting IL5RA or IL-5 are effective in reducing eosinophil levels and alleviating symptoms in these conditions. Given its specificity for eosinophil regulation, IL5RA is a critical target for therapeutic intervention in diseases characterized by eosinophilic inflammation.