IL1R2 encodes interleukin-1 receptor type 2, a non-signaling decoy receptor that dampens IL-1 pathway activity by sequestering IL-1 ligands and limiting productive signaling through IL1R1.[@colotta1993][@mantovani2001][@molgora2022] IL1R2 exists as both membrane-bound and soluble forms, enabling local and systemic control of inflammatory amplitude.[@colotta1993][@orlando2024]
In neurodegeneration, IL1R2 is best interpreted as a regulatory brake within broader neuroinflammatory circuits rather than a stand-alone disease driver. This is relevant to disorders where chronic innate immune activation contributes to progression, including [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and [multiple sclerosis](/diseases/multiple-sclerosis).[@heneka2021][@zhou2022]
IL1R2 encodes interleukin-1 receptor type 2, a non-signaling decoy receptor that dampens IL-1 pathway activity by sequestering IL-1 ligands and limiting productive signaling through IL1R1.[@colotta1993][@mantovani2001][@molgora2022] IL1R2 exists as both membrane-bound and soluble forms, enabling local and systemic control of inflammatory amplitude.[@colotta1993][@orlando2024]
In neurodegeneration, IL1R2 is best interpreted as a regulatory brake within broader neuroinflammatory circuits rather than a stand-alone disease driver. This is relevant to disorders where chronic innate immune activation contributes to progression, including [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and [multiple sclerosis](/diseases/multiple-sclerosis).[@heneka2021][@zhou2022]
Core Biology
Decoy Receptor Function
Unlike IL1R1, IL1R2 lacks a functional intracellular Toll/IL-1 receptor signaling domain and therefore does not propagate canonical pro-inflammatory signaling. Instead, IL1R2 reduces IL-1 bioavailability and signaling efficiency through ligand trapping and receptor-level interference.[@colotta1993][@mantovani2001]
Soluble IL1R2
Shedding and alternative processing generate soluble IL1R2, which can neutralize extracellular IL-1 and act as a distributed anti-inflammatory buffer.[@molgora2022][@orlando2024]
Cell-Type Context
IL1R2 is enriched in myeloid compartments, where it helps determine whether IL-1 signaling resolves or escalates.[@mantovani2001][@orlando2024] In the CNS, this logic maps to [microglia](/cell-types/microglia-neuroinflammation)-astrocyte inflammatory crosstalk, though direct cell-state atlases for IL1R2 in human neurodegeneration are still limited.[@heneka2021][@zhou2022]
Neurodegeneration-Relevant Interpretation
Alzheimer's Disease Context
IL-1 axis overactivation, inflammasome signaling, and sustained cytokine tone are recurrent findings in AD biology.[@heneka2021][@zhou2022] IL1R2 is therefore mechanistically relevant as an endogenous counter-regulator that may constrain excessive IL-1 signaling when induced.
Parkinson's And Related Disorders
In PD and atypical parkinsonism, inflammatory stress and microglial priming can worsen neuronal vulnerability.[@zhou2022] Within this framework, IL1R2 is a plausible resilience node: higher decoy capacity may reduce harmful IL-1 exposure, while inadequate IL1R2 response could permit persistent inflammatory amplification.
Evidence Boundaries
Direct causal IL1R2 intervention trials in AD/PD are not yet mature.
Most strong human IL1R2 data come from peripheral inflammatory diseases and sepsis severity studies.[@berton2025][@vannucchi2025]
Neurodegeneration inference is currently pathway-grounded, not fully phenotype-proven.
Translational Opportunities
Biomarker Use
IL1R2 (membrane or soluble) may be useful as part of a panel biomarker for inflammatory set-point, especially when paired with IL-1 pathway, inflammasome, and glial activation markers.[@berton2025][@vannucchi2025]
Therapeutic Concepts
Potential strategies include:
Enhancing endogenous IL1R2 expression in specific immune cell states.
Engineered soluble decoy approaches to titrate IL-1 burden.
Combination regimens pairing IL-1 axis modulation with disease-specific neuroprotective interventions.
These concepts remain investigational and require disease-stage and compartment-aware validation.
Research Priorities
Define IL1R2 expression trajectories in human brain and CSF datasets across AD/PD stages.
Test whether IL1R2 augmentation shifts microglial state transitions in iPSC-derived models.
Integrate IL1R2 metrics with longitudinal imaging and clinical progression outcomes.
Dissect how IL1R2 interacts with [NLRP3](/entities/nlrp3-inflammasome)-linked inflammatory cascades in [tau](/proteins/tau) and synuclein models.
[Colotta F, Re F, Muzio M, et al, Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4 (1993)](https://pubmed.ncbi.nlm.nih.gov/8287751/)
[Mantovani A, Locati M, Vecchi A, Sozzani S, Allavena P, Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines (2001)](https://pubmed.ncbi.nlm.nih.gov/11123040/)
[Molgora M, Barajon I, Mantovani A, Garlanda C, Regulation of the IL-1 system by IL-1R2 and IL-1R8 in disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35211118/)
[Orlando A, Cazzetta V, Pucino V, et al, Negative regulator IL-1R2 and its roles in immune regulation (2024)](https://pubmed.ncbi.nlm.nih.gov/38850793/)
[Heneka MT, Kummer MP, Latz E, Innate immune activation in neurodegenerative disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33670164/)
[Zhou Y, Ulland TK, Colonna M, Microglia and neuroinflammation in neurodegenerative disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35630670/)
[Berton M, Cani C, Milani G, et al, Monocyte-macrophage membrane IL-1R2 expression as a severity biomarker in sepsis (2025)](https://pubmed.ncbi.nlm.nih.gov/40204720/)
[Vannucchi A, Croci S, Dell'Oro V, et al, Structural and dynamic properties of IL-1 receptors (2025)](https://pubmed.ncbi.nlm.nih.gov/41415279/)