IL13RA1 Human

What is IL13RA1 and what are its primary functions in humans?

IL13RA1 is a receptor protein that forms part of the type II interleukin-4 receptor complex. It heterodimerizes with the interleukin receptor 4 alpha (IL-4Rα) to create a complex that can be activated by either IL-13 or IL-4. This receptor complex regulates peripheral allergic and anthelminthic immune responses . In the central nervous system, IL13RA1 is constitutively expressed in midbrain dopaminergic neurons, where its activation by IL-13 increases cellular susceptibility to oxidative stress . The protein plays dual roles in immune modulation and neuronal vulnerability, making it relevant to both inflammatory and neurodegenerative conditions.

How does IL13RA1 signaling differ from type I IL-4 receptor signaling?

IL13RA1 forms the type II IL-4 receptor along with IL-4Rα, while the type I IL-4 receptor consists of IL-4Rα paired with the common gamma chain. This structural difference creates distinct downstream signaling pathways with varying physiological outcomes. In experimental models, global expression profiling of lungs from mice stimulated with allergen or IL-4 has demonstrated that marker genes of alternatively activated macrophages are differentially regulated by the type I and type II IL-4 receptors . Specifically, while both receptor types can activate JAK-STAT pathways, the type II receptor (containing IL13RA1) uniquely mediates airway resistance, mucus production, TGF-β induction, and certain chemokine responses that are critical in asthma pathogenesis .

How is IL13RA1 expression regulated in different human tissues?

IL13RA1 shows constitutive expression in midbrain dopaminergic neurons and the substantia nigra in humans . During inflammation, IL13RA1 expression can be induced in microglial cells, creating vulnerability to IL-13-mediated damage . In the respiratory system, IL13RA1 expression controls responses to allergens, playing crucial roles in airway hyperresponsiveness and mucus production . The receptor's differential expression across tissues creates tissue-specific responses to IL-13 and IL-4, explaining the diverse pathologies associated with these cytokines.

What evidence links IL13RA1 to Parkinson's disease pathogenesis?

The human gene for IL13RA1 is located in chromosomal regions associated with Parkinson's disease (PD) . Several lines of evidence support this connection:

• IL13RA1 is constitutively expressed in midbrain dopaminergic neurons, which are the primary neurons affected in PD .

• IL-13 mediated activation of IL-13Rα1 increases cellular susceptibility to oxidative stress - a key pathological mechanism in PD .

• A specific mutation in IL13RA1 (rs145868092) causes a leucine to phenylalanine substitution at position 319, affecting a residue critical for IL-13 binding .

• This mutation confers a gain-of-function that increases neuronal vulnerability to oxidative stress, potentially increasing PD risk .

• Mice null for IL-13Rα1 are partially protected in inflammatory models of PD, suggesting the receptor's direct involvement in disease mechanisms .

How do IL13RA1 mutations affect dopaminergic neuron vulnerability to oxidative stress?

The missense mutation rs145868092 in IL13RA1 substitutes leucine at position 319 with phenylalanine (Leu319Phe), affecting a critical residue for IL-13 binding . Experimental evidence shows this mutation creates a gain-of-function phenotype that enhances neuronal susceptibility to multiple forms of oxidative stress:

• In human SH-SY5Y neurons, cells expressing the mutant IL13RA1Phe319 showed significantly higher cytotoxicity than those expressing wild-type IL13RA1Leu319 when exposed to hydrogen peroxide (H₂O₂) .

• Similar enhanced vulnerability was observed with t-butyl hydroperoxide (tBOOH) exposure, with significant differences at 2.5 and 5 ng/mL of IL-13 .

• Most notably, the mutation enhanced susceptibility to RSL3-induced ferroptosis, a form of regulated cell death implicated in PD pathogenesis .

These findings suggest that IL13RA1 mutations may contribute to PD by amplifying neuronal damage during inflammatory or oxidative conditions.

What methodological approaches best evaluate IL13RA1-related neuronal vulnerability?

To investigate IL13RA1's role in neuronal vulnerability, researchers have developed several methodological approaches:

• Cell culture models: Undifferentiated human SH-SY5Y cells represent a validated model for studying PD-related oxidative stress mechanisms . These cells can be transfected with wild-type or mutant IL13RA1 constructs to assess differential responses.

• Oxidative stress paradigms: Multiple oxidative stressors should be tested, including:

  • Hydrogen peroxide (H₂O₂) for general oxidative stress

  • t-butyl hydroperoxide (tBOOH) for lipid peroxidation

  • RSL3 for ferroptosis induction through glutathione peroxidase 4 inhibition

• Dose-response relationships: Testing multiple concentrations of both IL-13 (1-5 ng/mL) and oxidative stressors enables identification of synergistic effects and threshold responses .

• Cell death quantification: Methods like LDH release assays or fluorescent viability markers can quantify cytotoxicity under different experimental conditions.

• Signaling pathway analysis: Examination of Jak-Stat and PI3 kinase-mTOR pathways activated by IL-13Rα1 helps elucidate mechanistic details .

How does IL13RA1 regulate allergic airway inflammation?

IL13RA1 serves as a critical regulator of allergic airway inflammation through several key mechanisms:

• Chemokine production: IL13RA1 is essential for the induction of chemokines including CCL2, CCL11, CCL17, and CCL24 in response to both IL-13 and allergen challenge . In IL13RA1-deficient mice, there is a near-complete (approximately 99%) reduction in CCL2, CCL11, and CCL24 production and an 82% reduction in CCL17 following allergen challenge .

• Airway hyperresponsiveness: Both allergen-induced and IL-4-induced increases in airway resistance are completely dependent on IL13RA1 . IL13RA1-deficient mice fail to develop airway hyperresponsiveness in response to methacholine challenge after allergen or IL-4 exposure.

• Mucus production: IL13RA1 is critical for mucus hyperproduction, with IL13RA1-deficient mice showing approximately 80% reduction in PAS-positive cells (mucus-producing cells) following IL-4 challenge and complete absence of mucus induction after IL-13 challenge .

• TGF-β induction: The production of TGF-β, a key mediator of airway remodeling, is entirely dependent on IL13RA1 in response to both allergen and IL-13 challenge .

What is the relationship between IL13RA1 and IgE production?

IL13RA1 has a complex relationship with IgE production that varies between baseline conditions and allergic responses:

• Baseline IgE: IL13RA1 is essential for maintaining normal baseline IgE levels. IL13RA1-deficient mice exhibit barely detectable IgE levels under homeostatic conditions .

• Allergen-induced IgE: Despite the critical role in baseline IgE, IL13RA1-deficient mice can still mount a substantial IgE response to allergen challenge. While the levels are slightly (but statistically significantly) lower than in wild-type mice, they still develop a prominent IgE response .

• T cell-dependent antibody responses: Th2 responses and IgE production to T cell-dependent antigens appear to be IL13RA1-independent . This suggests that while IL13RA1 regulates homeostatic IgE, alternative pathways can compensate during active immune responses.

This differential requirement for IL13RA1 in baseline versus allergen-induced IgE production suggests distinct regulatory mechanisms for homeostatic and inflammatory antibody production.

How do IL13RA1-dependent and independent pathways contribute to eosinophilic inflammation?

Research has revealed a nuanced role for IL13RA1 in eosinophilic inflammation:

• IL13RA1-independent eosinophilia: Surprisingly, allergen-challenged IL13RA1-deficient mice still develop robust lung eosinophilia comparable to wild-type mice, despite dramatically reduced levels of eotaxins (CCL11 and CCL24) . This indicates the existence of CCR3- and IL13RA1-independent pathways for lung eosinophil recruitment.

• IL13RA1-dependent mediators: While eosinophil numbers remain intact, IL13RA1 controls the production of key inflammatory mediators including:

  • Eotaxins (CCL11, CCL24)

  • CCL2 (MCP-1)

  • CCL17 (TARC)

  • TGF-β

• Cytokine balance: IL13RA1-deficient mice maintain normal levels of IL-4 and IL-5 in bronchoalveolar lavage fluid after allergen challenge, but show increased levels of IL-10 and IL-13 . This altered cytokine profile may contribute to the maintenance of eosinophilia despite reduced chemokine production.

These findings highlight the complexity of inflammatory cell recruitment during allergic responses and suggest redundant mechanisms for eosinophil trafficking that function independently of IL13RA1.

What are the most effective methods for studying IL13RA1 genetic variants?

Studying IL13RA1 genetic variants requires a multi-faceted approach combining genetic identification and functional characterization:

• Genetic identification strategies:

  • Targeted sequencing of the IL13RA1 gene in cohorts with relevant phenotypes (e.g., early-onset Parkinson's disease)

  • Filtering for rare variants (MAF < 0.05) without other known disease mutations

  • Statistical analysis to determine disease association (Fisher's exact test, odds ratio calculation)

• In silico analysis:

  • Structural prediction to identify variants affecting functionally important residues

  • Evolutionary conservation analysis to prioritize potentially deleterious mutations

  • For example, rs145868092 affects amino acid 319, which is essential for IL-13 binding

• Functional characterization:

  • Cell-based assays with wild-type and mutant constructs

  • Assessment of ligand binding affinity

  • Downstream signaling pathway activation (Jak-Stat, PI3K-mTOR)

  • Vulnerability to oxidative stressors (H₂O₂, tBOOH, RSL3)

• Animal models:

  • Gene knockout studies (IL13RA1-/- mice)

  • Knock-in of specific human mutations

  • Challenge with relevant stimuli (allergens, inflammatory mediators, oxidative stressors)

How can researchers effectively analyze IL13RA1-dependent gene expression profiles?

Analysis of IL13RA1-dependent gene expression requires sophisticated genomic approaches:

• Experimental design considerations:

  • Comparison of wild-type and IL13RA1-deficient models

  • Multiple stimulation conditions (e.g., allergen, IL-4, IL-13)

  • Appropriate time points to capture primary and secondary response genes

  • Tissue-specific analysis (e.g., lung, brain regions)

• Gene expression profiling methods:

  • RNA sequencing for comprehensive transcriptome analysis

  • qRT-PCR validation of key differentially expressed genes

  • Cell-type specific analysis when possible (single-cell approaches)

• Data analysis strategies:

  • Identification of commonly and differentially regulated genes across stimuli

  • Pathway enrichment analysis

  • Comparison with established signature gene sets (e.g., alternatively activated macrophage markers)

  • Integration with protein expression data when available

• Validation of key findings:

  • Targeted gene knockdown or overexpression studies

  • Protein-level confirmation of expression changes

  • Functional relevance testing

Research has identified several IL13RA1-dependent genes across different stimulation conditions. For example, genes like Chia, Scin, Retnlb (Relm-β), Itlna, and Capn9 (Calpain 9) are similarly regulated by IL13RA1 after both IL-4 and allergen challenge, while other alternatively activated macrophage signature genes show differential IL13RA1 dependence between stimuli .

What cellular and animal models are most appropriate for IL13RA1 research?

Different research questions require specific model systems:

• Cellular models:

  • Human SH-SY5Y neuroblastoma cells: Validated for studying oxidative stress mechanisms relevant to Parkinson's disease

  • Primary human and murine dopaminergic neurons: More physiologically relevant but technically challenging

  • iPSC-derived dopaminergic neurons: Allow investigation with patient-specific genetic backgrounds

  • Bronchial epithelial cells: For studying mucus production and airway responses

  • Immune cells (macrophages, T cells, B cells): For investigating inflammatory mechanisms

• Mouse models:

  • IL13RA1 knockout mice: Essential for dissecting receptor-specific functions

  • Tissue-specific conditional knockouts: To avoid developmental confounders

  • Allergen challenge models (e.g., OVA, house dust mite): For studying asthma-like responses

  • MPTP or α-synuclein models: For studying PD-like neurodegeneration

  • Genetic models incorporating human IL13RA1 variants

• Model selection considerations:

  • Research question (neurodegeneration vs. inflammation)

  • Endpoint measurements required (behavioral, biochemical, histological)

  • Translational relevance to human disease

  • Technical feasibility and ethical considerations

The choice of model should be guided by the specific pathway or disease feature being investigated, with recognition that multiple models may be necessary for comprehensive understanding.

How might targeting IL13RA1 signaling provide therapeutic opportunities for neurodegenerative diseases?

Understanding IL13RA1's role in neurodegeneration opens several therapeutic avenues:

• Direct receptor antagonism:

  • Development of selective IL13RA1 antagonists to block IL-13 binding

  • Antibody-based approaches targeting the IL13RA1/IL-4Rα heterodimer

  • Small molecule inhibitors of the receptor's intracellular domain

• Downstream pathway modulation:

  • Targeting Jak-Stat and PI3 kinase-mTOR pathways activated by IL-13Rα1

  • Selective inhibition of neuronal versus immune cell signaling components

• Context-dependent intervention:

  • Agents that specifically block IL13RA1 signaling during oxidative stress conditions

  • Combination therapies targeting both inflammatory activation and oxidative damage

• Preventative approaches:

  • Genetic screening for high-risk IL13RA1 variants (e.g., rs145868092)

  • Early intervention in individuals with genetic susceptibility

  • Enhancement of antioxidant defenses in vulnerable populations

The challenge lies in developing interventions that protect neurons without compromising beneficial immune functions. Given that IL-13-mediated damage requires concomitant oxidative stress , therapeutic strategies might focus on this intersection rather than complete pathway blockade.

What mechanisms explain the paradoxical role of IL13RA1 in inflammation?

IL-13 is typically classified as an "anti-inflammatory" cytokine, yet IL13RA1 signaling can contribute to tissue damage - a paradox that requires mechanistic explanation:

• Cell type-specific effects:

  • IL-13 may downregulate inflammatory mediators in some immune cells while simultaneously increasing vulnerability in neurons and other cells expressing IL13RA1

  • This creates a situation where inflammation resolution may inadvertently damage bystander cells

• Context-dependent outcomes:

  • IL-13's effects depend on the presence of other signals, particularly oxidative stress

  • The timing of IL-13 signaling relative to other inflammatory events may determine beneficial versus detrimental outcomes

• Regulatory balance hypothesis:

  • IL-13 may damage cells that promote inflammation (including activated microglia expressing IL13RA1)

  • Dopaminergic neurons constitutively expressing IL13RA1 would be equally vulnerable

  • This suggests neuronal damage may result not only from inflammation itself but also from its down-regulation processes

• Long-term consequences of repeated exposures:

  • While individual inflammatory episodes might cause minimal damage, repeated events over time could lead to progressive neurodegeneration

  • Genetic variants enhancing IL13RA1 activity would increase this cumulative vulnerability

Understanding these mechanisms could help resolve the apparent contradiction between IL-13's anti-inflammatory classification and its contribution to tissue damage.

How do IL13RA1-dependent pathways intersect with ferroptosis in neurodegeneration?

Emerging evidence suggests important connections between IL13RA1 signaling and ferroptosis - a form of regulated cell death implicated in neurodegeneration:

• Experimental evidence:

  • IL-13 potentiates RSL3 toxicity in human SH-SY5Y cells

  • Both IL13 and IL13RA1 mutations associated with PD show enhanced potentiation of RSL3-induced cell death

• Mechanistic intersections:

  • IL-13 signaling may reduce glutathione levels or impair glutathione peroxidase activity

  • IL13RA1 activation could enhance lipid peroxidation, a key feature of ferroptosis

  • Shared vulnerability of dopaminergic neurons to both IL13RA1 activation and ferroptotic death

• Therapeutic implications:

  • Ferroptosis inhibitors (iron chelators, lipid peroxidation inhibitors) may protect against IL13RA1-mediated neurodegeneration

  • GSH-enhancing treatments that have shown benefits in PD clinical trials may work partly by attenuating IL13RA1-ferroptosis interactions

• Future research directions:

  • Detailed molecular mapping of how IL13RA1 signaling modifies ferroptotic pathways

  • Investigation of whether IL13RA1 genetic variants alter ferroptosis sensitivity

  • Development of targeted interventions at the IL13RA1-ferroptosis intersection

This emerging area represents a promising frontier in understanding how inflammatory signaling contributes to neurodegeneration through specific cell death mechanisms.

What are the most critical unanswered questions in IL13RA1 research?

Despite significant advances, several crucial questions remain in IL13RA1 research:

• How do genetic variants in IL13RA1 interact with environmental factors to modulate disease risk in both neurological and allergic conditions?

• What accounts for the tissue-specific effects of IL13RA1 signaling, particularly the unique vulnerability of dopaminergic neurons?

• Can IL13RA1-targeted therapies be developed that selectively protect vulnerable neurons without compromising beneficial immune functions?

• What mechanisms explain CCR3- and IL13RA1-independent pathways for lung eosinophilia, and how might these alternate pathways be targeted?

• How does the balance between type I and type II IL-4 receptors determine immune response outcomes in different disease contexts?

Addressing these questions will require interdisciplinary approaches spanning genetics, molecular biology, immunology, and neuroscience.

How might integrative approaches advance IL13RA1 research and therapeutic development?

Moving forward, integrative approaches offer the most promise for translating IL13RA1 research into clinical applications:

• Multi-omics integration:

  • Combining genomics, transcriptomics, proteomics, and metabolomics data to build comprehensive pathway models

  • Integration of epigenetic regulation information to understand context-specific receptor functions

• Systems biology modeling:

  • Computational models of IL13RA1 signaling networks in different cell types

  • Simulation of pathway perturbations to predict therapeutic effects and side effects

• Translational research pipelines:

  • Biobanking of patient samples with IL13RA1 variants

  • Development of patient-derived cellular models

  • Correlation of genetic variants with clinical outcomes in longitudinal studies

• Precision medicine approaches:

  • Genetic testing for IL13RA1 variants in high-risk populations

  • Personalized interventions based on individual IL13RA1 genotype and disease phenotype

  • Biomarker development to identify patients most likely to benefit from IL13RA1-targeted therapies

These integrated approaches promise to accelerate both basic understanding and therapeutic applications for IL13RA1-related disorders.