The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The requested target (IL36RN, UniProt Q9UBH0) corresponds to interleukin‑36 receptor antagonist (IL‑36Ra), a member of the IL‑1 cytokine superfamily that antagonizes IL‑36 receptor (IL‑36R) signaling; this mapping is explicit in multiple peer‑reviewed sources focused on IL‑36 biology and generalized pustular psoriasis (GPP). (krueger2024targetedreviewof pages 1-2, hawkes2023theroleof pages 1-3, macleod2016neutrophilelastasemediatedproteolysis pages 1-2)
IL36RN encodes IL‑36Ra, an endogenous antagonist within the IL‑36 cytokine subfamily that suppresses pro‑inflammatory responses at epithelial barrier sites, especially skin. (krueger2024targetedreviewof pages 1-2, fukaura2023targetingil36in pages 1-2)
IL‑36 agonists (IL‑36α/β/γ) signal through IL‑36R with recruitment of the accessory protein IL‑1RAcP, triggering downstream inflammatory pathways including MyD88, NF‑κB, and MAPK activation; IL‑36Ra binds the IL‑36 receptor complex but does not support productive accessory‑protein recruitment, thereby competitively inhibiting IL‑36 signaling. (macleod2016neutrophilelastasemediatedproteolysis pages 1-2, fukaura2023targetingil36in pages 1-2)
A 2023 review further summarizes that IL‑36Ra suppresses signaling by preventing IL‑36R/IL‑1RAcP dimerization and notes canonical downstream inflammatory signaling nodes (MAPK and NF‑κB). (li2023newinsightson pages 1-2)
Primary function: IL‑36Ra is a secreted/extracellular receptor antagonist that inhibits IL‑36R signaling and thereby attenuates IL‑36–driven inflammatory programs (e.g., chemokine induction that recruits neutrophils). (macleod2016neutrophilelastasemediatedproteolysis pages 1-2, li2023newinsightson pages 1-2)
A central regulatory concept in IL‑36 biology is protease‑dependent “licensing”: IL‑36 subfamily members are produced as precursors and require N‑terminal processing for full activity (agonist or antagonist). (fukaura2023targetingil36in pages 1-2, macleod2016neutrophilelastasemediatedproteolysis pages 1-2)
IL‑36Ra processing: A key primary study demonstrated that neutrophil elastase (but not other tested neutrophil proteases) cleaves IL‑36Ra into a highly active antagonistic form and that this processed IL‑36Ra more strongly suppresses IL‑36γ‑induced chemokines. (macleod2016neutrophilelastasemediatedproteolysis pages 1-2)
Experimental evidence: In human primary dermal fibroblasts, keratinocytes, and skin equivalents, elastase‑processed IL‑36Ra caused a dose‑dependent reduction of IL‑36γ‑induced IL‑8 and CCL20, supporting the model that proteolytic activation of IL‑36Ra can counter‑regulate neutrophilic inflammation. (macleod2016neutrophilelastasemediatedproteolysis pages 1-2)
Broader protease landscape (IL‑36 family): A 2023 skin‑focused review summarizes that IL‑36 precursor activation can be mediated by neutrophil proteases (cathepsin G, proteinase 3, elastase) and by cathepsin S released from keratinocytes/fibroblasts, and highlights endogenous protease inhibitors (SERPINA1/SERPINA3) as regulators of IL‑36 processing. (fukaura2023targetingil36in pages 1-2)
IL‑36 biology is concentrated at barrier tissues (skin prominently; also lung and gut). (li2023newinsightson pages 1-2)
In skin, IL‑36 agonists are mainly produced by keratinocytes in the epidermis, with additional production by dendritic cells, macrophages, endothelial cells, and dermal fibroblasts; IL‑36Ra functions at the receptor complex in the extracellular compartment where these cytokines act. (fukaura2023targetingil36in pages 1-2, macleod2016neutrophilelastasemediatedproteolysis pages 1-2)
Loss‑of‑function IL36RN variants cause deficiency of interleukin‑36 receptor antagonist (DITRA) and are strongly linked to severe pustular phenotypes including GPP, consistent with a mechanism of unopposed IL‑36 signaling and exaggerated neutrophilic inflammation. (okorie2024cutaneousfindingsand pages 11-12, macleod2016neutrophilelastasemediatedproteolysis pages 1-2)
A 2024 targeted review/meta‑analysis reported that IL36RN mutations are significantly more frequent in “GPP‑only” than in GPP with concomitant plaque psoriasis (OR 3.51; 95% CI 2.29–5.38). (krueger2024targetedreviewof pages 1-2)
In that synthesis, monoallelic IL36RN variants were reported in up to 33.3% of GPP patients and biallelic variants in up to 73.2%, compared with monoallelic 0%–11.9% and biallelic 0% in plaque psoriasis only. (krueger2024targetedreviewof pages 1-2)
Frequently reported variants included c.115+6T>C (p.Arg10ArgfsX1), c.227C>T (p.Pro76Leu), and c.338C>T (p.Ser113Leu), with geographic/ethnic variation (notably higher prevalence of the most frequent mutation in East Asian and Asian‑enriched studies). (krueger2024targetedreviewof pages 1-2)
A 2023 BioDrugs review summarizes IL‑36 cytokines as key regulators of innate and adaptive immunity in skin and highlights that anti‑IL‑36 agents (notably IL‑36R‑blocking antibodies) have been evaluated across multiple inflammatory dermatoses. (fukaura2023targetingil36in pages 1-2)
A 2023 Frontiers in Immunology review emphasizes that GPP is a rare, potentially life‑threatening inflammatory disease driven by abnormal activation of the IL‑36–chemokine–neutrophil axis, and reports prevalence estimates ranging approximately 2–120 cases per million. (hawkes2023theroleof pages 1-3)
The same review summarizes mortality estimates reported across studies (e.g., 0–3.3 deaths per 100 patient‑years) and notes a Japanese hospitalized cohort (N=1516) reporting 4.2% mortality. (hawkes2023theroleof pages 1-3)
The 2024 meta-analytic synthesis (above) provides a clearer basis for using IL36RN genotype to distinguish GPP subgroups and to motivate pathway‑targeted approaches. (krueger2024targetedreviewof pages 1-2)
Regulatory status: Spesolimab (anti‑IL‑36R monoclonal antibody) received US FDA approval in September 2022 for treatment of GPP flares in adults, with subsequent approvals in other regions; a 2024 review also notes more recent approval for subcutaneous dosing for treatment when not in flare (per label). (gwillim2024spesolimabforgeneralized pages 2-4)
Dosing for flares (as summarized in 2024 review): single 900 mg IV over 90 minutes, with an optional second 900 mg dose 1 week later if symptoms persist. (gwillim2024spesolimabforgeneralized pages 2-4)
A 2024 review summarizing the two trials supporting initial approval reported:
Phase 1 proof‑of‑concept (NCT02978690; n=7): 5/7 (71%) achieved GPPGA 0/1 by week 1 and 7/7 by week 4; mean GPPASI improvement was 59.0% at week 1, 73.2% at week 2, and 79.8% at week 4. (gwillim2024spesolimabforgeneralized pages 1-2, gwillim2024spesolimabforgeneralized pages 4-5)
Effisayil™1 (NCT03782792; phase 2, randomized): At week 1, GPPGA pustulation subscore 0 occurred in 19/35 (54%) with spesolimab vs 1/18 (6%) placebo (difference 49 percentage points; 95% CI 21–67; P<0.001). GPPGA total score 0/1 occurred in 15/35 (43%) vs 2/18 (11%) (difference 32 percentage points; 95% CI 2–53; P=0.02). (gwillim2024spesolimabforgeneralized pages 1-2, gwillim2024spesolimabforgeneralized media 67b8352d)
Safety statistic (week 1): infections were reported in 6/35 (17%) spesolimab vs 1/18 (6%) placebo. (gwillim2024spesolimabforgeneralized pages 1-2, gwillim2024spesolimabforgeneralized pages 5-6)
A 2024 Pharmaceutics review summarized Effisayil™2 (dose‑finding, 48 weeks; n=123), reporting flare occurrence by week 48 of 52% (placebo), 23% (low dose), 29% (medium dose), and 10% (high dose), with statistically significant superiority for time‑to‑flare (reported p=0.0005). (vilaca2024newandemerging pages 6-8, vilaca2024newandemerging pages 5-6)
A 2024 Pharmaceutics review summarized an open‑label phase 2 single‑arm study (GALLOP; n=8) reporting 75% clinical response by Clinical Global Impression at weeks 4 and 16, with 50% described as “very much improved.” (vilaca2024newandemerging pages 6-8)
A 2023 Frontiers in Immunology review explicitly frames GPP as driven by abnormal activation of the IL‑36–chemokine–neutrophil axis, providing a mechanistic justification for IL‑36R antagonism as a targeted therapy strategy. (hawkes2023theroleof pages 1-3)
Skin‑focused reviews emphasize that IL‑36 biology functions as a regulated system in which excessive agonist activity, reduced antagonist function (including IL36RN deficiency), and protease‑mediated activation together determine inflammatory outcomes—supporting two therapeutic concepts: (i) direct IL‑36R blockade (e.g., spesolimab) and (ii) upstream modulation of protease processing (e.g., elastase/cathepsin pathways). (fukaura2023targetingil36in pages 1-2, macleod2016neutrophilelastasemediatedproteolysis pages 1-2)
The following table consolidates the functional annotation and translational evidence for IL36RN/IL‑36Ra, emphasizing 2023–2024 sources.
| 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 | (krueger2024targetedreviewof pages 1-2, hawkes2023theroleof pages 1-3) |
| 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 | (fukaura2023targetingil36in pages 1-2, li2023newinsightson pages 1-2) |
| 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 | (macleod2016neutrophilelastasemediatedproteolysis pages 1-2, fukaura2023targetingil36in pages 1-2) |
| 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 | (fukaura2023targetingil36in pages 1-2, li2023newinsightson pages 1-2) |
| 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 | (krueger2024targetedreviewof pages 1-2, okorie2024cutaneousfindingsand pages 11-12) |
| 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 | (gwillim2024spesolimabforgeneralized pages 1-2, gwillim2024spesolimabforgeneralized pages 5-6, vilaca2024newandemerging pages 5-6, vilaca2024newandemerging pages 6-8, gwillim2024spesolimabforgeneralized pages 2-4, gwillim2024spesolimabforgeneralized media 67b8352d) |
| 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 | (hawkes2023theroleof pages 1-3, gwillim2024spesolimabforgeneralized pages 2-4) |
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.
References
(krueger2024targetedreviewof pages 1-2): James G. Krueger, Anna Pagotto, Samuel Haftel, and Birgit Gradl. Targeted review of il36rn mutations in patients with generalised pustular psoriasis. Skin Health and Disease, Mar 2024. URL: https://doi.org/10.1002/ski2.343, doi:10.1002/ski2.343. This article has 13 citations and is from a peer-reviewed journal.
(hawkes2023theroleof pages 1-3): Jason E. Hawkes, Sudha Visvanathan, and James G. Krueger. The role of the interleukin-36 axis in generalized pustular psoriasis: a review of the mechanism of action of spesolimab. Frontiers in Immunology, Nov 2023. URL: https://doi.org/10.3389/fimmu.2023.1292941, doi:10.3389/fimmu.2023.1292941. This article has 32 citations and is from a peer-reviewed journal.
(macleod2016neutrophilelastasemediatedproteolysis pages 1-2): Tom Macleod, Rosella Doble, Dennis McGonagle, Christopher W. Wasson, Adewonuola Alase, Martin Stacey, and Miriam Wittmann. Neutrophil elastase-mediated proteolysis activates the anti-inflammatory cytokine il-36 receptor antagonist. Scientific Reports, Apr 2016. URL: https://doi.org/10.1038/srep24880, doi:10.1038/srep24880. This article has 120 citations and is from a peer-reviewed journal.
(fukaura2023targetingil36in pages 1-2): Ryo Fukaura and Masashi Akiyama. Targeting il-36 in inflammatory skin diseases. BioDrugs, pages 1-15, Mar 2023. URL: https://doi.org/10.1007/s40259-023-00587-5, doi:10.1007/s40259-023-00587-5. This article has 44 citations and is from a peer-reviewed journal.
(li2023newinsightson pages 1-2): Minghui Li, Wei Jiang, Zehui Wang, Yihan Lu, and Jun Zhang. New insights on il‑36 in intestinal inflammation and colorectal cancer (review). Experimental and Therapeutic Medicine, Apr 2023. URL: https://doi.org/10.3892/etm.2023.11974, doi:10.3892/etm.2023.11974. This article has 10 citations and is from a peer-reviewed journal.
(okorie2024cutaneousfindingsand pages 11-12): Chiamaka L. Okorie, Krithika Nayudu, and Vinod E. Nambudiri. Cutaneous findings and treatments in deficiency of interleukin‐36 receptor antagonist (ditra): a review of the literature. Experimental Dermatology, Sep 2024. URL: https://doi.org/10.1111/exd.14934, doi:10.1111/exd.14934. This article has 15 citations and is from a domain leading peer-reviewed journal.
(gwillim2024spesolimabforgeneralized pages 2-4): Eran C. Gwillim and Anna J. Nichols. Spesolimab for generalized pustular psoriasis: a review of two key clinical trials supporting initial us regulatory approval. Frontiers in Immunology, Jul 2024. URL: https://doi.org/10.3389/fimmu.2024.1359481, doi:10.3389/fimmu.2024.1359481. This article has 17 citations and is from a peer-reviewed journal.
(gwillim2024spesolimabforgeneralized pages 1-2): Eran C. Gwillim and Anna J. Nichols. Spesolimab for generalized pustular psoriasis: a review of two key clinical trials supporting initial us regulatory approval. Frontiers in Immunology, Jul 2024. URL: https://doi.org/10.3389/fimmu.2024.1359481, doi:10.3389/fimmu.2024.1359481. This article has 17 citations and is from a peer-reviewed journal.
(gwillim2024spesolimabforgeneralized pages 4-5): Eran C. Gwillim and Anna J. Nichols. Spesolimab for generalized pustular psoriasis: a review of two key clinical trials supporting initial us regulatory approval. Frontiers in Immunology, Jul 2024. URL: https://doi.org/10.3389/fimmu.2024.1359481, doi:10.3389/fimmu.2024.1359481. This article has 17 citations and is from a peer-reviewed journal.
(gwillim2024spesolimabforgeneralized media 67b8352d): Eran C. Gwillim and Anna J. Nichols. Spesolimab for generalized pustular psoriasis: a review of two key clinical trials supporting initial us regulatory approval. Frontiers in Immunology, Jul 2024. URL: https://doi.org/10.3389/fimmu.2024.1359481, doi:10.3389/fimmu.2024.1359481. This article has 17 citations and is from a peer-reviewed journal.
(gwillim2024spesolimabforgeneralized pages 5-6): Eran C. Gwillim and Anna J. Nichols. Spesolimab for generalized pustular psoriasis: a review of two key clinical trials supporting initial us regulatory approval. Frontiers in Immunology, Jul 2024. URL: https://doi.org/10.3389/fimmu.2024.1359481, doi:10.3389/fimmu.2024.1359481. This article has 17 citations and is from a peer-reviewed journal.
(vilaca2024newandemerging pages 6-8): João Vilaça, Orhan Yilmaz, and Tiago Torres. New and emerging treatments for generalized pustular psoriasis: focus on il-36 receptor inhibitors. Pharmaceutics, 16:908, Jul 2024. URL: https://doi.org/10.3390/pharmaceutics16070908, doi:10.3390/pharmaceutics16070908. This article has 13 citations.
(vilaca2024newandemerging pages 5-6): João Vilaça, Orhan Yilmaz, and Tiago Torres. New and emerging treatments for generalized pustular psoriasis: focus on il-36 receptor inhibitors. Pharmaceutics, 16:908, Jul 2024. URL: https://doi.org/10.3390/pharmaceutics16070908, doi:10.3390/pharmaceutics16070908. This article has 13 citations.