IL17RA -interleukin 17 receptor A |Elisa - Clia - Antibody - Protein

Background

Interleukin-17 receptor A (IL17RA) is a protein critical for immune responses, especially in mediating host defense against extracellular pathogens and in inflammatory processes. IL17RA is the primary receptor for the IL-17 family of cytokines, a group known to play key roles in driving immune responses by recruiting neutrophils and promoting inflammation. Among the IL-17 family, IL-17A and IL-17F are particularly significant in immune signaling via IL17RA. IL-17 cytokines and their receptors have been extensively studied for their involvement in autoimmune diseases, inflammatory conditions, and some cancers, where dysregulated IL-17 signaling leads to excessive or persistent inflammation.

IL17RA, as a receptor, is broadly expressed across various cell types, including epithelial cells, fibroblasts, macrophages, and dendritic cells. This widespread expression pattern reflects the receptor’s role in both the immune and non-immune cells, enabling it to participate in the body's initial responses to infection and inflammation.

Protein Structure

The IL17RA protein consists of several structural domains optimized for cytokine binding and signal transduction. It is a type I transmembrane protein, organized into three main domains:

Extracellular Domain:

• The extracellular region of IL17RA contains fibronectin type III-like domains, which are essential for binding IL-17 family ligands. These domains facilitate the receptor’s interaction with IL-17A and IL-17F, which are the principal cytokines binding IL17RA with high affinity.
• Notably, the IL17RA extracellular domain has conserved cysteine residues that form disulfide bonds, providing structural stability necessary for ligand binding. This domain undergoes various post-translational modifications, including glycosylation, that enhance the receptor’s ligand affinity and stability.
• Glycosylation sites on IL17RA play an essential role in correct folding, stability, and surface expression. These sites are critical because the glycosylated extracellular domain’s structure directly impacts the receptor's function and ability to interact with its ligands.

Transmembrane Domain:

• The single-pass transmembrane region is hydrophobic, anchoring IL17RA in the cell membrane. This domain serves as the interface between the extracellular and intracellular domains, allowing signal transduction to occur when the receptor is activated by cytokine binding.
• The transmembrane region is crucial for receptor positioning and provides the spatial orientation needed for forming receptor complexes.

Intracellular (Cytoplasmic) Domain:

• The intracellular domain is essential for signaling and contains motifs required for activating downstream signaling pathways. Unlike many other cytokine receptors, IL17RA does not possess traditional tyrosine kinase domains or immunoreceptor tyrosine-based activation motifs (ITAMs). Instead, it uses other adapter proteins to initiate signal transduction.
• The cytoplasmic domain interacts with a set of proteins like Act1 (also known as TRAF3IP2), which is critical for initiating IL-17 signaling cascades. Act1 mediates the recruitment of other adapter proteins and signaling molecules, leading to the activation of pathways, including NF-κB, MAPKs, and C/EBP transcription factors. These pathways ultimately control the expression of pro-inflammatory cytokines, chemokines, and other immune effectors.

Classification and Subtypes

IL17RA is part of the IL-17 receptor family, which includes other members like IL17RB, IL17RC, IL17RD, and IL17RE. Among these receptors, IL17RA has the highest affinity for IL-17A and IL-17F, making it the principal receptor mediating IL-17-dependent responses.

In terms of functional pairing, IL17RA often forms heterodimers with IL17RC, which enhances its ligand-binding specificity and signaling potential. This IL17RA/IL17RC heterodimer is necessary for binding IL-17A and IL-17F and initiating downstream signaling cascades. This heterodimeric nature allows IL17RA to modulate responses specific to IL-17 cytokines, playing a vital role in inflammation and immunity.

Function and Biological Significance

IL17RA’s primary function is to mediate signaling for IL-17 family cytokines, particularly IL-17A and IL-17F, which are critical in pro-inflammatory responses:

Induction of Pro-Inflammatory Responses:

• IL17RA is a key receptor involved in inflammatory signaling. Binding of IL-17 cytokines to IL17RA induces downstream signaling pathways, which lead to the activation of NF-κB and MAPK pathways. These signaling cascades result in the production of various inflammatory mediators, including cytokines (e.g., TNF-α, IL-6), chemokines (e.g., CXCL1, CCL20), and antimicrobial peptides.
• IL17RA-mediated signaling recruits immune cells like neutrophils to infection sites, providing rapid innate immune responses to pathogens. The receptor’s ability to mediate responses across both immune and non-immune cells helps the body quickly respond to microbial invasions and contributes to the host defense against fungi and bacteria.

Role in Epithelial and Barrier Tissue Immunity:

• IL17RA expression in epithelial cells and fibroblasts allows it to participate in mucosal immunity, particularly in barrier tissues like the lungs, intestines, and skin. In these tissues, IL17RA plays a critical role in the production of antimicrobial peptides and mucins, which are essential for maintaining tissue integrity and preventing pathogen entry.
• Through the promotion of antimicrobial peptide production and neutrophil recruitment, IL17RA signaling is vital for host protection at mucosal surfaces, reducing the risk of infections at these vulnerable sites.

Contribution to Autoimmune and Chronic Inflammatory Diseases:

• While IL17RA-driven IL-17 signaling is essential for normal immune responses, dysregulation of IL-17 and IL17RA activity is implicated in various autoimmune and inflammatory diseases. Overactive IL-17 signaling can lead to chronic inflammation and is associated with diseases such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. In these diseases, IL17RA-mediated pathways perpetuate inflammatory cascades, leading to tissue damage and disease progression.
• Due to its involvement in autoimmunity, IL17RA is a therapeutic target in these conditions, with several biologic drugs aiming to block IL-17 signaling pathways to reduce inflammation and alleviate disease symptoms.

Clinical Issues

IL17RA has emerged as a significant target in the treatment of autoimmune diseases and chronic inflammatory conditions due to its central role in IL-17-driven inflammation:

Autoimmune Diseases:

• In autoimmune conditions such as psoriasis and ankylosing spondylitis, IL17RA contributes to chronic inflammation. IL-17 inhibitors, which target the IL17RA/IL-17A axis, are clinically approved for treating these diseases, helping to reduce inflammation and improve patient outcomes. Drugs like secukinumab and ixekizumab are anti-IL-17A antibodies that block IL17RA-mediated signaling, demonstrating efficacy in reducing symptoms of psoriasis and other IL-17-driven diseases.

Respiratory and Mucosal Infections:

• Given IL17RA’s role in mucosal immunity, patients receiving IL-17 inhibitors may be at higher risk for certain infections, particularly Candida and other fungal infections. This highlights the receptor’s critical function in immune defenses, especially at barrier tissues.

Cancer:

• IL17RA’s role in cancer is complex, as IL-17 signaling can have both pro-tumorigenic and anti-tumorigenic effects depending on the cancer type and immune environment. IL-17A signaling via IL17RA can promote chronic inflammation and contribute to a tumor-promoting environment, especially in gastrointestinal cancers. However, in some contexts, IL-17-induced immune activation can also enhance anti-tumor responses, especially in conjunction with therapies that boost immune cell activity.

Therapeutic Targeting:

• Targeting IL17RA and the IL-17 signaling pathway is an area of active clinical research for inflammatory diseases. While anti-IL-17 therapies have been effective in treating conditions like psoriasis, there is ongoing research into small molecule inhibitors and antibody therapies that can selectively inhibit IL17RA or its downstream signaling components. These interventions aim to more precisely modulate IL-17 responses and improve therapeutic outcomes while minimizing side effects.

Summary

IL17RA is a vital receptor in the immune system, mediating the effects of IL-17 cytokines that are crucial for inflammatory and immune responses. Structurally, IL17RA consists of an extracellular domain with fibronectin type III-like domains for cytokine binding, a transmembrane region, and a cytoplasmic domain that initiates signaling pathways, primarily through adapter proteins like Act1. IL17RA’s function in recruiting neutrophils, promoting cytokine production, and defending against pathogens at mucosal surfaces underscores its role in immune responses and inflammation.

In terms of disease, dysregulated IL17RA signaling is implicated in autoimmune and chronic inflammatory diseases such as psoriasis and rheumatoid arthritis, where it drives persistent inflammation. Targeted IL-17 inhibitors have demonstrated efficacy in these conditions, offering relief for patients by dampening IL-17-driven pathways. However, IL17RA signaling is also essential for protecting mucosal tissues, and patients treated with IL-17 inhibitors may be more susceptible to certain infections.

IL17RA remains an important focus in immunology and clinical research, with ongoing studies exploring the therapeutic potential of modulating IL-17 signaling in diverse diseases, including autoimmune conditions, cancer, and infection-related inflammation.