| Aspect | Key points (1-2 sentences) | Representative evidence (include what was measured/observed) | Key recent sources (2023-2024 prioritized) with URL and publication month/year | Context IDs |
|---|---|---|---|---|
| Identity/definition | **IL36RN** encodes **interleukin-36 receptor antagonist (IL-36Ra)**, the natural antagonist of the IL-36 pathway in humans; this matches UniProt **Q9UBH0** and the IL-1 family context. In GPP-focused reviews, IL-36Ra is described as a suppressor of proinflammatory responses whose insufficiency permits neutrophil-dominant sterile pustular inflammation. | Reviews describe IL36RN as the gene encoding IL-36Ra and note that dysregulated IL-36 signaling drives neutrophil infiltration and pustule formation in generalized pustular psoriasis (GPP). | Krueger et al., *Skin Health and Disease* (Mar 2024), https://doi.org/10.1002/ski2.343; Hawkes et al., *Frontiers in Immunology* (Nov 2023), https://doi.org/10.3389/fimmu.2023.1292941 | (pqac-00000010, pqac-00000008) |
| Molecular mechanism of antagonism | IL-36Ra binds the same receptor axis as IL-36 agonists but prevents productive signaling; mechanistically, it blocks formation of the signaling-competent IL-36R/IL-1RAcP complex and thereby suppresses downstream **MyD88–NF-κB/MAPK** activation. This is the primary molecular function of IL36RN. | Experimental and review evidence indicates IL-36Ra binds IL-36R without accessory-protein recruitment; downstream inflammatory outputs such as chemokines/cytokines are consequently reduced. One review additionally notes higher-affinity/slower-off-rate receptor binding than agonists and prevention of receptor dimerization. | Fukaura & Akiyama, *BioDrugs* (Mar 2023), https://doi.org/10.1007/s40259-023-00587-5; Li et al., *Experimental and Therapeutic Medicine* (Apr 2023), https://doi.org/10.3892/etm.2023.11974 | (pqac-00000004, pqac-00000005) |
| Proteolytic processing/activating proteases | Like other IL-1 family cytokines, IL-36Ra requires **N-terminal processing** for full antagonistic activity. For IL-36Ra specifically, **neutrophil elastase** cleaves the precursor into a highly active antagonistic form; by contrast, IL-36 agonists are activated by proteases including cathepsin G, proteinase 3, elastase, and cathepsin S. | In primary human dermal fibroblasts, keratinocytes, and skin equivalents, cleaved IL-36Ra reduced **IL-36γ-induced IL-8 and CCL20** more effectively than full-length IL-36Ra; the 2016 study identified elastase, but not other tested neutrophil proteases, as the activating protease for IL-36Ra. Reviews summarize broader IL-36-family protease control and SERPINA1/SERPINA3 inhibition of elastase/cathepsin G. | Macleod et al., *Scientific Reports* (Apr 2016), https://doi.org/10.1038/srep24880; Fukaura & Akiyama, *BioDrugs* (Mar 2023), https://doi.org/10.1007/s40259-023-00587-5 | (pqac-00000013, pqac-00000009) |
| Expression/localization (skin/barrier tissues, cell types) | IL-36 biology is centered at **barrier tissues**. Recent reviews place IL-36 ligands/receptor broadly in **skin, lung, and intestine**, with skin-relevant production from **keratinocytes**, dendritic cells, macrophages, endothelial cells, and dermal fibroblasts; IL-36Ra functions extracellularly at the receptor complex in these barrier environments. | Reviews report that IL-36α/γ are mainly expressed by keratinocytes in epidermis, with additional production by dendritic cells, macrophages, endothelial cells, and dermal fibroblasts; IL-36 ligands and IL-36R are broadly expressed at mucosal/barrier sites. In COPD, airway studies found increased IL-36γ in epithelial-derived compartments and decreased IL-36Ra in bronchoalveolar/nasal fluid, supporting extracellular pathway imbalance. | Fukaura & Akiyama, *BioDrugs* (Mar 2023), https://doi.org/10.1007/s40259-023-00587-5; Li et al., *Experimental and Therapeutic Medicine* (Apr 2023), https://doi.org/10.3892/etm.2023.11974 | (pqac-00000009, pqac-00000005) |
| Disease genetics (DITRA/GPP; mutation frequencies and notable variants) | Loss-of-function **IL36RN** variants cause **DITRA** and are strongly enriched in GPP, especially GPP without plaque psoriasis. Recent meta-analytic review found monoallelic variants in up to **33.3%** and biallelic variants in up to **73.2%** of GPP patients, versus **0%-11.9%** monoallelic and **0%** biallelic in plaque psoriasis only; common variants include **c.115+6T>C (p.Arg10ArgfsX1)**, **c.227C>T (p.Pro76Leu)**, and **c.338C>T (p.Ser113Leu)**. | Meta-analysis reported a significantly higher IL36RN mutation rate in **GPP-only vs GPP+plaque psoriasis** (**OR 3.51, 95% CI 2.29-5.38**). Case-based DITRA review documents pathogenic homozygous variants and notes that IL-36 ligands and IL-36Ra require proteolytic processing for full activity. | Krueger et al., *Skin Health and Disease* (Mar 2024), https://doi.org/10.1002/ski2.343; Okorie et al., *Experimental Dermatology* (Sep 2024), https://doi.org/10.1111/exd.14934 | (pqac-00000003, pqac-00000007) |
| Therapeutic targeting (spesolimab approvals; Effisayil 1 and phase 1 response rates; Effisayil 2 flare prevention; imsidolimab early data) | **Spesolimab** is a first-in-class anti-IL-36R monoclonal antibody approved first by the **US FDA in Sep 2022** for adult GPP flares, with later approvals in other regions and more recent subcutaneous maintenance approval. Clinical efficacy is rapid in acute flares and promising for flare prevention; **imsidolimab (ANB019)** has shown early activity but less mature evidence. | **Phase 1 proof-of-concept:** **5/7 (71%)** achieved **GPPGA 0/1 by week 1**, **7/7 by week 4**; mean **GPPASI** improved **59.0% (wk1), 73.2% (wk2), 79.8% (wk4)**, with no severe/serious AEs reported. **Effisayil 1:** week-1 **GPPGA pustulation 0** in **19/35 (54%)** on spesolimab vs **1/18 (6%)** placebo (**difference 49 percentage points; 95% CI 21-67; P<0.001**); **GPPGA total 0/1** in **15/35 (43%)** vs **2/18 (11%)** (**difference 32 points; 95% CI 2-53; P=0.02**); infections at week 1 in **17% vs 6%**. **Effisayil 2:** over 48 weeks, flares occurred in **52% placebo**, **23% low-dose**, **29% medium-dose**, and **10% high-dose** spesolimab; time-to-flare superiority reported (**p=0.0005**). **Imsidolimab:** open-label GALLOP study (**n=8**) reported **75%** clinical response at weeks 4 and 16, with **50%** rated “very much improved.” | Gwillim & Nichols, *Frontiers in Immunology* (Jul 2024), https://doi.org/10.3389/fimmu.2024.1359481; Vilaça et al., *Pharmaceutics* (Jul 2024), https://doi.org/10.3390/pharmaceutics16070908 | (pqac-00000016, pqac-00000018, pqac-00000014, pqac-00000015, pqac-00000020, pqac-00000022) |
| Epidemiology/mortality stats for GPP | GPP is rare but clinically serious, and IL36RN biology is most clearly translated in this disease context. Recent reviews estimate prevalence at roughly **2-120 cases per million**, with reported mortality ranging from **0-3.3 deaths per 100 patient-years** in some studies; a Japanese hospitalized cohort (**N=1516**) reported **4.2% mortality**. | Review text summarizes regional prevalence variability and mortality, and emphasizes that severe flares may require emergency or inpatient care because of complications such as sepsis, heart failure, renal failure, and death. | Hawkes et al., *Frontiers in Immunology* (Nov 2023), https://doi.org/10.3389/fimmu.2023.1292941; Gwillim & Nichols, *Frontiers in Immunology* (Jul 2024), https://doi.org/10.3389/fimmu.2024.1359481 | (pqac-00000008, pqac-00000011) |


*Table: This table summarizes verified human IL36RN/IL-36Ra biology, disease genetics, and translational evidence, emphasizing 2023-2024 reviews and clinical data. It is useful as a compact evidence map connecting core function to therapeutics such as spesolimab.*