IL-1R1 (IL1R1)

The primary signal-transducing receptor for IL-1β and IL-1α. IL-1R1 is a single-pass type I membrane protein that, upon ligand binding, recruits the co-receptor IL-1RAcP (encoded by IL1RAP) to form the functional ternary signalling complex. This complex then recruits MyD88, triggering the IRAK1/4 → TRAF6 → NF-κB / MAPK cascade — the canonical signalling pathway for both interleukins, their shared endogenous antagonist IL-1Ra, and a convergence point for therapeutic IL-1 axis blockade (anakinra, rilonacept).

Identity

UniProt: P14778 (IL1R1_HUMAN) — Swiss-Prot (manually curated); accessed 2026-05-06
NCBI Gene: 3554 (symbol: IL1R1; synonyms IL1R, IL1RA, IL1RT1)
HGNC: 5993
Ensembl: ENSG00000115594
Mouse ortholog: Il1r1 (one-to-one)
Gene locus: 2q12.1
Common names: CD121a; p80 (from its ~80 kDa apparent MW); IL-1R type I

Naming note

“IL-1RA” and “IL1RA” appear as NCBI Gene synonyms for IL1R1 (the receptor) — not to be confused with IL1RN, the gene encoding IL-1Ra (IL-1 receptor antagonist). The file il-1r1.md is the canonical page for the signalling receptor; [[il-1ra]] covers the antagonist ligand.

Structure and domains

IL-1R1 is a 569-amino acid (human) type I single-pass transmembrane glycoprotein ¹²:

Region	Residues (approx.)	Structure
Extracellular	1–336	Three tandem immunoglobulin-like C2-type domains (D1–D3)
Transmembrane	337–356	Single helix
Intracellular	357–569	TIR domain (Toll/IL-1 receptor homology domain); NADase activity reported

The three extracellular Ig-like domains (D1–D3) form the ligand-binding scaffold; D1–D2 make primary contact with IL-1 ligands, while D3 is critical for IL-1RAcP co-receptor recruitment ². Six N-linked glycosylation sites account for the discrepancy between the ~47 kDa predicted MW and the ~80 kDa apparent MW on SDS-PAGE.

Key PTMs:

Tyr496 phosphorylation — creates a binding site for the p85 subunit of PI3-kinase, linking IL-1R1 to the PI3K–Akt pathway ²
N-glycosylation at six asparagines — required for proper folding and surface expression (UniProt P14778)

Soluble form: Proteolytic ectodomain shedding releases a soluble IL-1R1 (sIL-1R1; ~50–55 kDa) that retains ligand-binding capacity and may act as a decoy receptor in some contexts. Circulating sIL-1R1 levels are measureable in serum. needs-replication — the physiological role of sIL-1R1 vs the dedicated decoy receptor IL-1R2 in modulating extracellular IL-1 tone is incompletely defined.

Ligand selectivity

IL-1R1 binds three canonical IL-1 family cytokines with fundamentally different outcomes ³:

Ligand	Gene	Outcome	Notes
IL-1β	IL1B	Full agonist — recruits IL-1RAcP, activates signalling	Primary pathological ligand in inflammaging
IL-1α	IL1A	Full agonist — recruits IL-1RAcP, activates signalling	Alarmin; released by necrotic cells and senescent SASP
IL-1Ra	IL1RN	Competitive antagonist — binds IL-1R1 without recruiting IL-1RAcP; blocks both IL-1α and IL-1β	Basis for anakinra (recombinant IL-1Ra) therapeutics

The critical distinction: IL-1Ra binds IL-1R1 but, unlike IL-1α and IL-1β, fails to recruit IL-1RAcP to the complex — cross-linking experiments show no anti-IL-1RAcP-immunoprecipitable species when IL-1Ra is used as ligand ⁴. This failure to engage the accessory protein explains the absence of agonist signalling. Later structural work identified the “beta-bulge” loop of IL-1β (sequence QGEESN) as the structural element required for IL-1RAcP recruitment, and showed that inserting this loop into IL-1Ra partially converts it to an agonist — but this structural attribution is from post-1995 crystallographic studies, not Greenfeder et al. needs-citation — primary source for beta-bulge/QGEESN swap experiment needed.

Signalling cascade

Upon IL-1α or IL-1β binding, IL-1R1 undergoes a conformational change that recruits the co-receptor IL-1RAcP (IL-1 receptor accessory protein; encoded by IL1RAP), forming the ternary signalling complex ⁴. This brings the two cytoplasmic TIR domains into proximity for adaptor recruitment.

Canonical MyD88–NF-κB arm:

IL-1α/β → IL-1R1 + IL-1RAcP (ternary complex)
  → MyD88 recruitment via TIR–TIR interaction [^wesche1997]
  → IRAK4 auto-phosphorylation + IRAK1 activation     ([[irak4]])
  → TRAF6 (E3 ubiquitin ligase) K63-ubiquitin chain formation     ([[traf6]])
  → TAK1 (MAP3K7) + TAK1-binding proteins (TAB1/2/3)     ([[tak1]])
  → IKK complex (IKKα/β/γ) → IκBα phosphorylation/degradation
  → NF-κB nuclear translocation → IL-6, TNF, COX-2, iNOS, MMP transcription

MAPK arm (parallel):

TAK1 → MKK3/6 → p38 MAPK     ([[tak1]])
TAK1 → MKK4/7 → JNK
→ AP-1 transcription, cytokine mRNA stabilisation

PI3K arm:

Tyr496-phospho-IL-1R1 → PI3K-p85 recruitment → Akt activation [^boraschi2013]
→ cell survival, mTOR pathway integration

This converges with NF-κB pathway and MAPK pathway pages; the IL-1R1-specific proximal events (TIR–TIR, MyD88 recruitment) are described here as the canonical home.

Aging and inflammaging context

IL-1R1 is the primary effector receptor through which the two dominant IL-1 family alarmins of aged tissue drive inflammaging:

IL-1β from NLRP3 inflammasome activation — aged macrophages and monocytes show chronically elevated NLRP3 priming (constitutive NF-κB activation from accumulated DAMPs), resulting in exaggerated IL-1β output to weak stimuli. This output acts on IL-1R1 in stromal, endothelial, and immune cells to amplify the inflammatory milieu.
IL-1α from the SASP — Senescent cells constitutively produce IL-1α as an alarmin component of the senescence-associated secretory phenotype (SASP). IL-1α signals in autocrine and paracrine fashion through IL-1R1 to sustain NF-κB activation and maintain the SASP amplification loop.
IL-1R1 → NF-κB → more SASP — IL-1R1 signalling in senescent cells is itself NF-κB–activating, creating a positive feedback: SASP-derived IL-1α/β → IL-1R1 → NF-κB → more IL-6, IL-8, MMP secretion ⁵. For the cardiovascular output of this axis, see canakinumab and chronic-inflammation.

Dimension	Status
Pathway conserved in humans?	yes — IL1R1, IL1RAP, MYD88, IRAK1/4, TRAF6 all conserved with high homology
Phenotype (inflammaging) conserved in humans?	yes — CANTOS demonstrates the IL-1 axis causally mediates cardiovascular events in humans
Replicated in humans?	yes (CANTOS cardiovascular endpoint); partial (SASP-IL-1α loop in human senescence — mechanistic data largely in vitro)

CANTOS cross-reference

The CANTOS trial (Ridker et al. 2017, NEJM; n=10,061) tested canakinumab (anti-IL-1β mAb) rather than direct IL-1R1 blockade, but the trial result constitutes the strongest human evidence that IL-1 signalling through IL-1R1 is causally relevant to age-associated cardiovascular events ⁵. For per-arm effect sizes (HR, p-values, infection adverse events), see canakinumab — that page is the canonical home for CANTOS numerics.

Therapeutic landscape

Agent	Mechanism	Specificity	Status
Anakinra	Recombinant IL-1Ra	Blocks IL-1R1 (both IL-1α and IL-1β blocked)	FDA-approved (RA, CAPS, SJIA, NOMID)
Rilonacept	IL-1 Trap (Fc–IL-1R1–IL-1RAcP fusion protein)	Sequesters IL-1α + IL-1β	FDA-approved (CAPS, recurrent pericarditis)
canakinumab	Anti-IL-1β mAb (IgG1κ)	IL-1β-specific; upstream of IL-1R1	FDA-approved (CAPS, SJIA, gout); CANTOS phase 3
Anti-IL-1R1 mAbs (isunakinra; investigational)	Block IL-1R1 directly	IL-1α + IL-1β blocked (like anakinra)	Phase 1–2 (asthma, atopic dermatitis)

Anakinra vs rilonacept on IL-1R1: Both block IL-1R1 engagement by both ligands. Anakinra is the recombinant IL-1Ra that competes directly for the IL-1R1 binding groove; rilonacept is a circulating decoy that captures free IL-1α and IL-1β before they reach cell-surface IL-1R1.

For compound-level PK, dosing, and aging-context trial data, see canakinumab (verified R12) and the implicit stubs anakinra, rilonacept.

Mouse genetics

Il1r1-deficient mice — viable; resistant to LPS-induced fever; reduced mortality in septic shock models; arthritis severity substantially reduced in collagen-induced arthritis (CIA) and K/BxN serum-transfer models. The resistance to both exogenous IL-1 and endogenous inflammasome-driven IL-1 effects closely mirrors the pharmacology of IL-1Ra (anakinra) in humans. unsourced — precise citation for the original Il1r1-/- characterisation (likely Labow et al. 1997 or Horai et al. 1998) needs confirmation.
Aged Il1r1-/- mice — reduced age-related neuroinflammation and preserved cognitive function in some models, consistent with the NLRP3→IL-1β→IL-1R1 inflammaging loop. needs-replication

Dimension	Status
Pathway conserved in humans?	yes
Phenotype conserved in humans?	yes — anakinra reduces inflammation in human diseases mirroring the mouse CIA model
Replicated in humans?	yes (pharmacological; anakinra FDA-approved)

Pathway membership and cross-references

il-1-signaling — primary pathway page for the full IL-1 axis (verified R27): full ligand+receptor+MyD88-IRAK-NF-κB cascade integration; IL-1R1 is the receptor anchor for the agonist-driven branch
nf-kb — major downstream effector arm
ras-mapk — parallel MAPK arm (p38, JNK)
nlrp3-inflammasome — upstream of IL-1β production that drives IL-1R1 signalling
chronic-inflammation — hallmark context; IL-1R1 is the principal transducer of IL-1-driven inflammaging
cellular-senescence — SASP-derived IL-1α signals via IL-1R1 to maintain senescent cell NF-κB activation
caspase-1 — processes pro-IL-1β that activates IL-1R1
il-1b — primary agonist ligand (verified R13/R25)
il-1a — co-equal agonist, dominant alarmin in SASP (co-seeded sibling, R25 Tier B)
il-1ra — endogenous antagonist; mechanism basis for anakinra (co-seeded sibling, R25 Tier B)
canakinumab — anti-IL-1β mAb; indirectly blocks IL-1R1 activation (verified R12)
pyroptosis — terminal outcome when GSDMD pores exceed threshold during IL-1β secretion

Limitations and gaps

GTEx aging correlation: Not yet populated. IL1R1 expression changes with age across tissues are not established from GTEx API lookup in this seeding pass. needs-replication (gtex-aging-correlation: null)
Mendelian randomisation: No MR study has been identified that tests IL1R1 expression levels as causal for aging-related outcomes (cardiovascular disease, frailty). mr-causal-evidence: not-tested needs-replication
GenAge entry: IL1R1 is not listed in GenAge-human or GenAge-models as of this seeding pass (no aging gene entry found). Its relevance to inflammaging is indirect — through its role as the receptor for the primary SASP cytokines.
Il1r1-/- aging phenotype: Primary citation for the original Il1r1-/- characterisation needs confirmation; claim is consistent with consensus but flagged #gap/unsourced. Aged Il1r1-/- cognitive-protection data needs a specific primary source. needs-replication
Soluble IL-1R1 biology in aging: The circulating sIL-1R1 pool may buffer IL-1α/β tone in aged tissue, but quantitative data on how sIL-1R1 levels change with age are sparse. needs-replication
IL-1-signaling pathway page: RESOLVED 2026-05-07 (R27 propagation) — [[il-1-signaling]] is now seeded and verified, centralizing the full ligand–receptor–adaptor cascade. IL-1R1’s role as described here is the canonical content for the receptor subunit specifically; pathway-level cascade biology lives on [[il-1-signaling]].
Task-supplied DOI mismatches (BUG-2): Two DOIs provided in the seeding task did not match their claimed papers in the archive:
- 10.1111/imr.12015 — resolves to “Dynamics of NK cell interactions in vivo” (2012), not a Boraschi/Tagliabue IL-1 family review. Not cited.
- 10.1002/eji.201746939 — resolves to “Contact sensitizers trigger human CD1-autoreactive T-cell responses” (2017), not a Dinarello IL-1 family overview. Not cited.
- Replacement references used: Boraschi & Tagliabue 2013 Sem Immunol (doi:10.1016/j.smim.2013.10.023; confirmed) and Dinarello 2009 Annu Rev Immunol (doi:10.1146/annurev.immunol.021908.132612; confirmed).

Footnotes

doi:10.1126/science.2969618 · Sims JE et al. · Science 1988 · in-vitro (cDNA expression cloning, COS cell expression) · first molecular cloning of IL-1R1; established it as a member of the immunoglobulin superfamily; ~890 citations ↩
doi:10.1016/j.smim.2013.10.023 · Boraschi D & Tagliabue A · Semin Immunol 2013 · review · comprehensive coverage of the IL-1 receptor family structure, ligand specificity, and signalling; describes the three Ig-like domain architecture and co-receptor recruitment mechanism; ~236 citations ↩ ↩² ↩³
doi:10.1146/annurev.immunol.021908.132612 · Dinarello CA · Annu Rev Immunol 2009 · review · immunological and inflammatory functions of the IL-1 family; covers IL-1R1 signalling in depth; most-cited IL-1 family overview (~3388 citations) ↩
doi:10.1074/jbc.270.23.13757 · Greenfeder SA et al. · J Biol Chem 1995 · in-vitro (molecular cloning, binding studies) · cloned IL-1RAcP as the second subunit of the IL-1R1 complex required for signal transduction; showed IL-1Ra occupies the IL-1R1 binding site without recruiting IL-1RAcP; structural basis of antagonism; ~638 citations ↩ ↩²
doi:10.1056/NEJMoa1707914 · Ridker PM et al. · NEJM 2017 · rct · n=10,061 · phase 3; double-blind; post-MI patients with hsCRP ≥2 mg/L; three doses of canakinumab (50 mg, 150 mg, 300 mg q3m) vs placebo; median follow-up 3.7 years; primary endpoint nonfatal MI/stroke/CV death; 150 mg was the only dose meeting the prespecified significance threshold (HR 0.85, 95% CI 0.74–0.98, P=0.021); no LDL reduction; higher fatal infection rate with canakinumab; all-cause mortality neutral (HR 0.94, P=0.31); human proof-of-concept that IL-1β axis blockade reduces age-associated cardiovascular events independently of lipid lowering; local PDF: · for per-arm effect sizes see canakinumab ↩ ↩²

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