Cited by 206Inflammasome and immune disordersImmune Response and InflammationCell death mechanisms and regulation

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Intracellular Interleukin-1 Receptor 2 Binding Prevents Cleavage and Activity of Interleukin-1α, Controlling Necrosis-Induced Sterile Inflammation

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Zheng, Yue, Humphry, Melanie, Maguire, Janet J., Bennett, Martin R., Clarke, Murray C.H.·2013·Immunity

DOI 10.1016/j.immuni.2013.01.008PMC PMC3659285

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Abstract

Necrosis can induce profound inflammation or be clinically silent. However, the mechanisms underlying such tissue specificity are unknown. Interleukin-1α (IL-1α) is a key danger signal released upon necrosis that exerts effects on both innate and adaptive immunity and is considered to be constitutively active. In contrast, we have shown that necrosis-induced IL-1α activity is tightly controlled in a cell type-specific manner. Most cell types examined expressed a cytosolic IL-1 receptor 2 (IL-1R2) whose binding to pro-IL-1α inhibited its cytokine activity. In cell types exhibiting a silent necrotic phenotype, IL-1R2 remained associated with pro-IL-1α. Cell types possessing inflammatory necrotic phenotypes either lacked IL-1R2 or had activated caspase-1 before necrosis, which degraded and dissociated IL-1R2 from pro-IL-1α. Full IL-1α activity required cleavage by calpain after necrosis, which increased its affinity for IL-1 receptor 1. Thus, we report a cell type-dependent process that fundamentally governs IL-1α activity postnecrosis and the mechanism allowing conditional release of this blockade.

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Immune-related signature identifies IL1R2 as an immunological and prognostic biomarker in pancreatic cancer
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“[38] At the same time, some studies have preliminarily identified the role of IL1R2 in the development of cancers.”
Result
Baker's yeast beta glucan supplementation was associated with an improved innate immune mRNA expression response after exercise.
McFarlin, B., Bridgeman, E. A., Curtis, J. H., Vingren, J., & Hill, D. W. (2024) · Methods · doi:10.1016/j.ymeth.2024.07.013 · Cited by 6
Systemic and CSF Interleukin-1α Expression in a Rabbit Closed Cranium Subarachnoid Hemorrhage Model: An Exploratory Study
Croci, D. M., Wanderer, S., Strange, F., Grüter, B. E., Casoni, D. C., Sivanrupan, S., Widmer, H. R., Santo, S. D., Fandino, J., Mariani, L., et al. (2019) · Brain Sciences · doi:10.3390/brainsci9100249 · Cited by 8
Role of Interleukin 1 Receptor 2 in Kidney Disease
Hu, H., Wu, A., Mu, X., & Zhou, H. (2024) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2023.0172 · Cited by 7
“In addition, there is an intracellular IL-1R2 that blocks the maturation of intracellular IL-1 a precursor (pro-IL-1 a ), and this effect is lost by speciﬁc cleavage of IL-1R2 by activated IL-1 converting enzyme (caspase-1) (Zheng et al., 2013).”
Interleukin-1α activation and localization in lipopolysaccharide-stimulated human monocytes and macrophages
Carlsen, T. G., Kjærsgaard, P., Jørgensen, T. L., Foldbjerg, R., Lausen, M., Poulsen, T. B. G., Zabieglo, K., Christiansen, G., & Birkelund, S. (2015) · Journal of Immunological Methods · doi:10.1016/j.jim.2015.03.025 · Cited by 7
CCR8 Expression on Regulatory T Cells Reveals Trajectories of Tissue Adaptation and Protects Against Myocardial Infarction–Induced Tissue Damage
Li, N., Hao, Z., Yang, H., Cai, J., Liu, M., He, J., Gao, R., Shen, Y., Chen, Z., Lu, Y., et al. (2026) · Circulation · doi:10.1161/circulationaha.125.076426 · Cited by 6
Gene deletion of Interleukin-1α reduces ER stress-induced CHOP expression in macrophages and attenuates the progression of atherosclerosis in apoE-deficient mice.
Almog, T., Keshet, R., Kandel-Kfir, M., Shaish, A., Apte, R., Harats, D., & Kamari, Y. (2023) · Cytokine · doi:10.1016/j.cyto.2023.156212 · Cited by 6
Human vascular smooth muscle cells utilise chymase for the atypical cleavage and activation of Interleukin-1β
Morales-Maldonado, A., Humphry, M., Figg, N. L., & Clarke, M. C. H. (2023) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2023.117308 · Cited by 6
Self-citation
Beyond Negative Regulation: IL‐1R8 and IL‐1R2 as Novel Immune Checkpoints
Supino, D., Garuti, R., & Garlanda, C. (2025) · European Journal of Immunology · doi:10.1002/eji.70050 · Cited by 6
Targeting interleukin-1 signaling for renoprotection
Bogdanova, D. A., Samsonov, M. Y., Lebedeva, S. A., Bukhanova, D., Materenchuk, M. Y., & Mutig, K. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1591197 · Cited by 5
The Interleukin-1 Family
Garlanda, C., & Jaillon, S. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-374279-7.10001-3 · Cited by 5
A spatiotemporal atlas of senescence-associated secretory phenotype in fracture healing: stage-dependent mechanisms and therapeutic windows
Chen, B., Li, G., Fang, Q., Ding, P., & Gao, Y. (2026) · Inflammation and Regeneration · doi:10.1186/s41232-026-00416-6 · Cited by 5
“During cell necrosis, IL-1α is passively released into the extracellular environment, where it rapidly activates neighboring cells and amplifies the inflammatory cascade [102].”
Prologue: About DAMPs, PAMPs, and MAMPs
Land, W. G. (2018) · Springer eBooks · doi:10.1007/978-3-319-78655-1_11 · Cited by 5
Inflammatory Markers Combined With Metalloproteinase-9, Neopterin, and S100B Concentrations May Indicate the Pathogenesis of Central Nervous System Diseases in Children
Lubarski, K., Mania, A., Małecki, P., Mazur‐Melewska, K., & Figlerowicz, M. (2022) · Journal of Child Neurology · doi:10.1177/08830738221106663 · Cited by 4
“In the latter, neopterin reflected the fever duration and disease course, whereas CRP level did not.(32,33) Neopterin, as a sensitive cell-mediated Th1-dependent immunologic pathway marker, appears promptly after infection of mainly viral etiology.”
Background
Therapeutic targeting of inflammasome signaling by blocking interleukin-1
Coll, R. C. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-91802-2.00010-4 · Cited by 3
IL1R2 promotes retinal angiogenesis to participate in retinopathy of prematurity by activating the HIF1α/PFKFB3 pathway.
Zhou, N., Liu, L., & Li, Q. (2023) · Experimental Eye Research · doi:10.1016/j.exer.2023.109750 · Cited by 4
TLR2-dependent and independent pyroptosis in dTHP-1 cells induced by Actinomyces oris MG-1
Wu, Z., Takigawa, H., Maruyama, H., Nambu, T., Mashimo, C., & Okinaga, T. (2024) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2024.101680 · Cited by 4
“Therefore, the upregulation of IL-1R2 is perceived as a negative feedback mechanism [21].”
Background
CRISPR/Cas9 mediated mutation of mouse IL-1α nuclear localisation sequence abolishes expression
Daniels, M. J. D., Adamson, A. D., Humphreys, N. E., & Brough, D. (2017) · Scientific Reports · doi:10.1038/s41598-017-17387-x · Cited by 4
Bone Marrow-Derived IL-1Ra Increases TNF Levels Poststroke
von Linstow, C. U., Hindkjær, S. M., Nielsen, P. V., Degn, M., Lambertsen, K. L., Finsen, B. R., & Clausen, B. H. (2021) · Cells · doi:10.3390/cells10040956 · Cited by 4
“Here, we show by qPCR that BM cells, which have infiltrated the neural parenchyma [11], significantly downregulate a panel of harmful stroke-related mRNAs such as Arg, a marker of poor functional outcome and stroke severity [54], Cxcr2, which plays a role in immune cell trafficking during inflammation [55,56], Fpr1, w…”
Hyper-induction of IL-6 after TLR1/2 stimulation in calves with bovine respiratory disease
Reid, C., Donlon, J. D., Rémot, A., Kennedy, E., MATTEIS, G. D., O’Farrelly, C., McAloon, C. G., & Meade, K. G. (2024) · PLoS ONE · doi:10.1371/journal.pone.0309964 · Cited by 3
Abelson Helper Integration Site 1 haplotypes and peripheral blood expression associates with lithium response and immunomodulation in bipolar patients
Sakrajda, K., Bilska, K., Czerski, P. M., Narożna, B., Dmitrzak‐Węglarz, M., Heilmann‐Heimbach, S., Brockschmidt, F. F., Herms, S., Nöthen, M. M., Cichon, S., et al. (2023) · Psychopharmacology · doi:10.1007/s00213-023-06505-5 · Cited by 3
“On the other hand, the pro-IL1A interaction with inhibitory IL1R2 receptor may reduce or even prevent inflammation (Chen et al. 2007; Zheng et al. 2013; Di Paolo and Shayakhmetov 2016).”
Background
Endogenous DAMPs, Category III: Inducible DAMPs (Cat. III DAMPs)
Land, W. G. (2018) · Springer eBooks · doi:10.1007/978-3-319-78655-1_14 · Cited by 3
Bgh/GelMA/CMCS hydrogel with bone MSC-EVs for lunate defect repair
Li, M., Hu, H., Liu, L., Tian, M., & Li, X. (2025) · Nanomedicine · doi:10.1080/17435889.2025.2513852 · Cited by 2
Analysis of the effects of importin α1 on the nuclear translocation of IL-1α in HeLa cells
Yamada, A., Wake, K., Imaoka, S., Motoyoshi, M., Yamamoto, T., & Asano, M. (2024) · Scientific Reports · doi:10.1038/s41598-024-51521-w · Cited by 2
Cancer immunotherapy via nucleic acid aptamers
Zahedipour, F., Majeed, M. A., Kesharwani, P., & Sahebkar, A. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-85881-6.00003-8 · Cited by 2
The common IL1A single nucleotide polymorphism rs17561 is a hypomorphic mutation that significantly reduces interleukin‐1α release from human blood cells
Wiggins, K. A., Pyrillou, K., Humphry, M., Butterworth, A. S., & Clarke, M. C. H. (2022) · Immunology · doi:10.1111/imm.13584 · Cited by 2
“IL-1α is canonically cleaved by calpain, which occurs upon necrosis in some cell types and significantly increases activity [9], whilst IL-1β is typically activated by caspase-1 after inflammasome engagement [10].”
BackgroundInfluentialSelf-citation
Aptamers for Targeted Therapy
Yang, G. H., & Huang, Y. (2021) · Springer eBooks · doi:10.1007/978-981-33-4838-7_6 · Cited by 1
Screening Assays to Characterize Novel Endothelial Regulators Involved in the Inflammatory Response
Higueras, M. Á., Jiménez-García, L., Herranz, S., Hortelano, S., & Luque, A. (2017) · Journal of Visualized Experiments · doi:10.3791/55824 · Cited by 1
The Interplay between Transcription Factors and Epigenetic Modifications in Th2 Cells
Onodera, A., Kokubo, K., & Nakayama, T. (2018) · InTech eBooks · doi:10.5772/intechopen.73027 · Cited by 1
Regulation of Immunity and Disease by the IL-1 Receptor Family Members IL-1R2 and IL-1R8
Molgora, M., Supino, D., & Garlanda, C. (2018) · Springer eBooks · doi:10.1007/978-3-319-77658-3_10 · Cited by 1
The Growing World of DAMPs
Land, W. G. (2020) · Springer eBooks · doi:10.1007/978-3-030-53868-2_3 · Cited by 1
Frontiers in Clinical Drug Research - Alzheimer Disorders
Atta-ur-rahman, Mavoungou, C., Zimmerman, K. S., Wright, J., Harding, J., Cavallaro, R., Fuso, A., Yoshiyama, Y., Asija, Z., Clifford, A., et al. (2015) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/97816810806801150301 · Cited by 1
The impact of inflammatory and immune response-related genetic variants on prostate cancer risk among men of African descent.
Jones, D. (2014) · doi:10.18297/etd/1745 · Cited by 1
“lymphocyte, macrophage), as shown in Figure 3 [139, 141, 142].”
Background
Interleukin-1 Receptor Antagonist: A Promising Cytosine In Human Squamous Epithelial Cell CarcinomaPreprint
Ding, Y., Yi, J., Wang, J., & Sun, Z. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4192428 · Cited by 1
The Interleukin-1 Family
Garlanda, C., Ceglie, I. D., & Jaillon, S. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00178-2 · Cited by 1
The IL-1 family in relation to psoriasis
Doble, R. (2014) · White Rose eTheses Online (University of Leeds, The University of Sheffield, University of York)
Papel de inflamassomas e vias lisossomais na morte celular e resposta imune induzidas pela flagelina.
Lage, S. L. (2016) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.42.2016.tde-25022016-095353
The Function of IL-1α a Typical Alarmin
Asano, M. (2020) · Japanese Journal of Oral Diagnosis / Oral Medicine · doi:10.15214/jsodom.33.189
Differential anti-cancer signaling exerted by an in silico-designed compound in tumorigenic and non-tumorigenic breast cells
Visagie, M. H. (2014) · UpSpace Institutional Repository (University of Pretoria)
Ejes inflamatorios y alarminas en el intestino delgado en enfermedad celíaca
Pérez, F. (2021) · El Servicio de Difusión de la Creación Intelectual (National University of La Plata) · doi:10.35537/10915/129881
Research Progress of Different Inflammatory Factors in Osteoporosis
卢, 锋. (2022) · Advances in Clinical Medicine · doi:10.12677/acm.2022.124373
NLRP3 inflammasome: significance and potential therapeutic targets to advance solid organ transplantation
Karsalari, P. D., Asnaashari, K., & Rezaei, N. (2025) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2025.2500425
“Furthermore, IL-1 engages with adjacent cells to upregulate adhesion molecules and inflammatory cytokine and chemokine release such as IL-6, CXCL8 (IL-8), and CCL20 to augment more immune cells, leading to alloreactivity [164–166].”
Additional file 8 of Respirable stone particles differ in their ability to induce cytotoxicity and pro-inflammatory responses in cell models of the human airways
Grytting, V. S., Refsnes, M., Øvrevik, J., Halle, M. S., Schönenberger, J., van der Lelij, R., Snilsberg, B., Skuland, T., Blom, R., & Låg, M. (2021) · Figshare · doi:10.6084/m9.figshare.14552102
Defining the boundaries of a healthy immune response using standardized immune monitoring tools
Urrutia, A. (2017) · theses.fr (ABES) · doi:10.70675/ab3d67edz85e0z4bb0za3a8z4ce8116e8156
“…cytokines such as interferon-alpha (IFN-a), interferon-beta (IFN-b), interferon-gamma (IFN-g), tumor necrosis factor-alpha (TNF-a), interleukin 1-beta (IL-1b), and interleukin 23 (IL-23) (Dinarello, 2012; González-Navajas et al., 2012; Oppmann et al., 2000; Platanias, 2005; Zheng et al., 2013).”
Plasticité cellulaire et initiation tumorale dans le modèle du cancer du sein
Blander, H. D. (2020) · theses.fr (ABES) · doi:10.70675/c6b4eda8z19a5z4b3dzb7d9zacc5fd814b21

Authors: Zheng, Y., Humphry, M., Maguire, J. J., Bennett, M. R., & Clarke, M. C. H.
Affiliations: University of Cambridge (GB)
Corresponding author: Clarke, Murray C.H.
ORCID: Zheng, Yue
Maguire, Janet J.
Bennett, Martin R.
Clarke, Murray C.H.
Venue: Immunity
Publisher: Elsevier BV
Published: 2013-02
Volume: 38
Issue: 2
Pages: 285-295
ISSN: 1074-7613 (ISSN-L)
DOI: 10.1016/j.immuni.2013.01.008
PMC: PMC3659285
OpenAlex: W2038182824
Cited by: 205
References: 54
Citations by year: 2026: 6 · 2025: 10 · 2024: 15 · 2023: 11 · 2022: 18 · 2021: 15 · 2020: 6 · 2019: 14 · 2018: 15 · 2017: 17 · 2016: 18 · 2015: 20 · 2014: 18 · 2013: 22
FWCI: 11.65
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/3.0/ (vor, 165 d)
Locations: Immunity (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
Apollo (University of Cambridge) (submittedVersion, cc-by)
Apollo (cc-by)
Funders: National Institute for Health and Care Research
British Heart Foundation (RG/08/009/25841, PG/06/024/20354, FS/13/3/30038, RG04/001, FS/09/005/26845)
NIHR Cambridge Biomedical Research Centre
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords: interleukin-1 alpha, interleukin-1 receptor 2, sterile inflammation, necrosis, caspase-1, calpain, IL-1 receptor 1, damage-associated molecular patterns
MeSH terms: Animals, Calpain, Cell Line, Gene Expression Regulation, Humans, Inflammation, Necrosis, Organ Specificity, Protein Binding, Protein Precursors, Signal Transduction, Caspase 1, Mice, Receptors, Interleukin-1 Type II, Interleukin-1alpha, Proteolysis

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Intracellular Interleukin-1 Receptor 2 Binding Prevents Cleavage and Activity of Interleukin-1α, Controlling Necrosis-Induced Sterile Inflammation

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