Gene Number: 149233

Location: 1p31.3

Key Functions: Inflammatory signaling, T-helper 17 (Th17) cell regulation, immune response modulation, autoimmune disease susceptibility

IL23R encodes the interleukin-23 receptor (IL-23R), a transmembrane receptor that plays a pivotal role in shaping both innate and adaptive immune responses. It serves as the primary binding site for interleukin-23 (IL-23), a heterodimeric cytokine composed of p19 and p40 subunits, and mediates its biological effects through the activation of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathways. IL-23R signaling is essential for the differentiation, expansion, and maintenance of Th17 cells, a subset of CD4⁺ T cells critical for mucosal defense but also implicated in autoimmune and chronic inflammatory diseases.

Upon IL-23 binding, IL-23R associates with IL-12Rβ1 to form a functional receptor complex that activates JAK2 and TYK2, leading to the phosphorylation of STAT3, STAT4, and other downstream transcription factors. This cascade enhances the expression of Th17 effector cytokines, including IL-17A, IL-17F, and IL-22, which collectively drive neutrophil recruitment, epithelial activation, and inflammatory amplification. Under physiological conditions, these mechanisms play vital roles in maintaining barrier integrity and protecting against bacterial and fungal infections at mucosal sites such as the gut, respiratory tract, and skin.

IL-23R signaling contributes to immune function through multiple tightly regulated processes:

1. Th17 cell maintenance and expansion:IL-23R is indispensable for sustaining the Th17 lineage by preventing apoptosis and enhancing the secretion of pro-inflammatory cytokines. This ensures robust defense against pathogens but also increases susceptibility to autoimmune inflammation when dysregulated.

   
   

2. Inflammatory response modulation:Through STAT3 activation, IL-23R promotes the transcription of inflammatory mediators that perpetuate immune cell recruitment and cytokine release. Chronic activation of this pathway can lead to persistent inflammation and tissue damage.

   
   

3. Balance between effector and regulatory immunity:IL-23R signaling counteracts the differentiation of regulatory T cells (Tregs) and promotes a pro-inflammatory immune profile. This balance between Th17 and Treg populations is a key determinant of immune tolerance versus pathology.

   
   

Genetic variants in IL23R have been robustly associated with susceptibility to autoimmune and inflammatory diseases. The most extensively studied variant, Arg381Gln (rs11209026), results in a hypofunctional receptor with reduced STAT3 activation and attenuated Th17 responses. This variant confers protective effects against conditions such as Crohn’s disease, ulcerative colitis, ankylosing spondylitis, and psoriasis. Conversely, gain-of-function variants or increased IL-23R expression can enhance inflammatory signaling, heightening the risk for autoimmune pathogenesis and chronic tissue inflammation.

The IL-23/IL-23R axis represents a cornerstone of modern immunopathology and therapeutic intervention. Pharmacological blockade of this pathway has demonstrated significant efficacy in clinical treatment. Monoclonal antibodies targeting either IL-23 or its receptor—such as ustekinumab, guselkumab, and risankizumab—effectively suppress Th17-mediated inflammation and are now standard treatments for psoriasis, psoriatic arthritis, and inflammatory bowel diseases. These therapies highlight the pathogenic importance of IL-23R signaling and its central role in maintaining the delicate equilibrium between immune defense and self-tolerance.

In summary, IL23R encodes a critical mediator of Th17-driven immunity, functioning at the crossroads of host defense and inflammatory pathology. Its precise regulation is essential for protecting mucosal barriers while preventing excessive immune activation. Genetic and functional alterations in IL-23R profoundly influence disease susceptibility, making this receptor a key molecular link between inflammation, autoimmunity, and therapeutic immune modulation.