<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Interleukin-1 Alpha (IL-1α)</th></tr>
<tr><td><strong>Protein Name</strong></td><td>Interleukin-1 alpha</td></tr>
<tr><td><strong>Gene Symbol</strong></td><td>[IL1A](/genes/il1a)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td><a href="https://www.uniprot.org/uniprot/P01546" target="_blank">P01546</a></td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>17 kDa (pro-IL-1α), 12 kDa (mature)</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cytoplasm, membrane-bound, secreted</td></tr>
<tr><td><strong>Protein Family</strong></td><td>IL-1 family (IL-1α, IL-1β, IL-1RA)</td></tr>
<tr><td><strong>Brain Expression</strong></td><td>Astrocytes, [Microglia](/cell-types/microglia-neuroinflammation), neurons, endothelial cells</td></tr>
<tr><td><strong>Receptor</strong></td><td>IL-1R1 (canonical), IL-1R2 (decoy)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">109 edges</a></td>
</tr>
</table>
</div>
<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Interleukin-1 Alpha (IL-1α)</th></tr>
<tr><td><strong>Protein Name</strong></td><td>Interleukin-1 alpha</td></tr>
<tr><td><strong>Gene Symbol</strong></td><td>[IL1A](/genes/il1a)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td><a href="https://www.uniprot.org/uniprot/P01546" target="_blank">P01546</a></td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>17 kDa (pro-IL-1α), 12 kDa (mature)</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cytoplasm, membrane-bound, secreted</td></tr>
<tr><td><strong>Protein Family</strong></td><td>IL-1 family (IL-1α, IL-1β, IL-1RA)</td></tr>
<tr><td><strong>Brain Expression</strong></td><td>Astrocytes, [Microglia](/cell-types/microglia-neuroinflammation), neurons, endothelial cells</td></tr>
<tr><td><strong>Receptor</strong></td><td>IL-1R1 (canonical), IL-1R2 (decoy)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">109 edges</a></td>
</tr>
</table>
</div>
Interleukin-1 alpha (IL-1α) is a potent pro-inflammatory cytokine of the IL-1 family that plays a central role in initiating and amplifying inflammatory responses throughout the body and the central nervous system (CNS). Unlike its close relative [IL-1β](/proteins/il1b-protein), IL-1α is constitutively expressed in many tissues, including the brain, and functions critically as an alarmin — an endogenous danger signal released from damaged or dying cells to alert the immune system[@shaftel2023]. In neurodegenerative diseases, IL-1α drives chronic neuroinflammation that contributes to [amyloid-beta](/proteins/amyloid-beta) accumulation, tau pathology, synaptic dysfunction, and progressive neuronal death in both [Alzheimer's disease](/diseases/alzheimers-disease) (AD) and [Parkinson's disease](/diseases/parkinsons-disease) (PD)[@griffin2020].
IL-1α signals primarily through the IL-1R1 receptor, a member of the toll-like receptor (TLR) superfamily, which recruits the IL-1 receptor accessory protein (IL-1RAcP) to form a signaling complex that activates MyD88-dependent downstream pathways including [NF-κB](/entities/nf-kb), MAPK (ERK, p38, JNK), and AP-1 transcription factors[@sims2022]. This cascade triggers a broad transcriptional response that amplifies inflammation, upregulates adhesion molecules on endothelial cells, promotes leukocyte infiltration into the CNS, and induces other pro-inflammatory cytokines — creating a feed-forward loop that sustains chronic neuroinflammation[@brough2022].
The human IL1A gene encodes a 271-amino acid precursor protein (pro-IL-1α, approximately 31 kDa) that undergoes limited proteolytic processing to generate the mature, biologically active 17 kDa form (159 amino acids)[@sims2022]. The protein adopts the characteristic β-trefoil fold shared by all IL-1 family members, consisting of a bundle of six alpha-helices arranged in a compact globular structure that mediates receptor binding.
The N-terminal region of pro-IL-1α contains several notable features:
IL-1α undergoes several post-translational modifications that modulate its activity:
The crystal structure of IL-1α bound to IL-1R1 reveals that the cytokine engages the receptor through two distinct binding interfaces — a high-affinity site (site 1) and a lower-affinity site (site 2) that stabilizes the receptor complex[@sims2022]. Formation of the trimeric signaling complex (IL-1α:IL-1R1:IL-1RAcP) brings the intracellular TIR domains of both receptors into proximity, enabling MyD88 recruitment and downstream signal propagation.
In the healthy brain, IL-1α is expressed at low levels and performs several important physiological functions:
Neurodevelopment: IL-1α signaling is required for normal neural development. During embryonic and early postnatal development, IL-1α regulates neural progenitor cell proliferation in the subventricular zone and dentate gyrus, influences synaptic pruning and plasticity, and modulates the formation of neural circuits[@shaftel2023]. Mice lacking IL-1R1 show deficits in hippocampal-dependent learning and memory, suggesting that IL-1α signaling is involved in synaptic plasticity mechanisms including [long-term potentiation](/mechanisms/long-term-potentiation) (LTP).
Homeostatic brain function: Low-level IL-1α signaling contributes to normal cognitive function through its effects on hippocampal plasticity. The cytokine modulates neurogenesis, astrocyte reactivity, and blood-brain barrier (BBB) maintenance. Under normal conditions, these effects are tightly regulated by endogenous IL-1 receptor antagonist (IL-1RA), which competitively blocks IL-1R1 without triggering signal transduction.
CNS injury response: Following acute CNS injury (trauma, stroke, infection), IL-1α is rapidly released from damaged neurons and glia as part of the sterile inflammatory response. This alarmin function initiates a coordinated repair response: recruitment of immune cells to the injury site, activation of astrocytes and microglia to clear debris, and promotion of reactive gliosis to wall off damaged tissue[@zhang2022]. This acute response is self-limiting under normal conditions but can become chronic in neurodegenerative disease.
In the healthy CNS, IL-1α expression is documented in:
IL-1α is consistently elevated in Alzheimer's disease brains and cerebrospinal fluid (CSF), with particularly high levels observed in regions of pathological burden such as the hippocampus and entorhinal cortex[@griffin2020]. Key findings from human studies include:
IL-1α contributes to Alzheimer's disease through multiple interconnected mechanisms:
IL-1α directly promotes the amyloidogenic processing of [APP](/entities/app-protein) through upregulation of [BACE1](/entities/bace1) (β-secretase 1)[@liu2024]. In cell culture and animal models, IL-1α treatment increases BACE1 expression at both mRNA and protein levels via NF-κB-dependent transcriptional activation. This shift increases the rate of Aβ production from APP, accelerating amyloid plaque formation. Additionally, IL-1α may suppress Aβ clearance by reducing microglial phagocytosis and degrading enzyme expression.
IL-1α drives chronic microglial activation — the "M1" or "primed" pro-inflammatory phenotype characterized by production of TNF-α, [IL-6](/proteins/il6-protein), [CXCL8](/entities/cxcl8), and reactive oxygen/nitrogen species[@shaftel2023]. Chronically activated microglia are less effective at clearing amyloid deposits while simultaneously producing neurotoxic factors that damage synapses and neurons. IL-1α also promotes the formation of disease-associated microglia (DAM) that show altered homeostatic functions.
In AD, IL-1α-induced microglial activation creates a feed-forward loop: damaged neurons release IL-1α, which activates microglia to release more IL-1α and other cytokines, driving further neuronal damage. This self-sustaining inflammatory cascade is a hallmark of the "inflammaging" phenotype seen in aging brains and is thought to be a major driver of sporadic AD progression.
IL-1α promotes tau hyperphosphorylation and aggregation through multiple pathways[@wang2023]. First, IL-1α activates several kinases known to phosphorylate tau, including GSK-3β, CDK5, and p38 MAPK, through the NF-κB and MAPK signaling cascades. Second, IL-1α disrupts the activity of protein phosphatases (particularly PP2A) that normally dephosphorylate tau. Third, IL-1α exacerbates endoplasmic reticulum stress, which contributes to kinase activation. The resulting accumulation of hyperphosphorylated tau leads to neurofibrillary tangle formation and progressive neuronal dysfunction.
IL-1α impairs synaptic plasticity directly. In hippocampal slice cultures, IL-1α application blocks LTP induction, and chronic IL-1α exposure produces deficits in spatial memory that mirror those seen in early AD[@shaftel2023]. The mechanism involves IL-1R1 signaling in hippocampal neurons, which suppresses NMDA receptor function, alters AMPA receptor trafficking, and disrupts spine morphology. These effects occur before overt neuronal death and may underlie the earliest cognitive deficits in AD.
IL-1α is a potent disruptor of the [blood-brain barrier](/entities/blood-brain-barrier). IL-1α signaling on brain endothelial cells upregulates matrix metalloproteinases (MMP-2, MMP-9), which degrade tight junction proteins (claudin-5, occludin, ZO-1), leading to increased BBB permeability[@zhang2022]. This breakdown allows peripheral immune cells (T cells, monocytes) to enter the CNS, further amplifying neuroinflammation, and permits plasma proteins (fibrinogen, thrombin) that have neurotoxic effects to enter the brain parenchyma.
The IL-1 pathway is actively being targeted in AD clinical trials:
IL-1α is elevated in the [substantia nigra pars compacta](/brain-regions/substantia-nigra) and CSF of Parkinson's disease patients, and IL-1α levels correlate with disease severity, measured by Unified Parkinson's Disease Rating Scale (UPDRS) scores[@chen2022].
IL-1α is directly toxic to dopaminergic neurons in the substantia nigra. In primary neuron cultures and organotypic brain slices, IL-1α treatment induces dopaminergic neuron death through caspase-dependent and caspase-independent (necroptosis, ferroptosis) pathways[@chen2022]. The toxicity is mediated through IL-1R1 signaling in neurons, which activates MAPK pathways (particularly p38 and JNK), leading to mitochondrial dysfunction, increased reactive oxygen species (ROS) production, and activation of apoptotic cascades.
IL-1α also sensitizes dopaminergic neurons to other insults. Neurons pre-treated with IL-1α show dramatically increased vulnerability to [6-hydroxydopamine](/entities/6-hydroxydopamine) (6-OHDA), [MPTP](/entities/mptp-mpp), and alpha-synuclein pre-formed fibrils (PFFs), suggesting that IL-1α creates a permissive environment for disease progression.
Like in AD, IL-1α drives chronic microglial activation in PD, producing a neurotoxic milieu that damages dopaminergic neurons[@kim2024]. Activated microglia in the substantia nigra release TNF-α, IL-6, nitric oxide (NO), and superoxide, all of which are directly toxic to dopaminergic terminals and cell bodies. IL-1α also promotes microglial phagocytosis of dopaminergic synapses, contributing to early terminal loss before overt neuronal death.
IL-1α may accelerate α-synuclein aggregation and spread. In cell culture models, IL-1α treatment increases α-synuclein expression, promotes its phosphorylation at Ser-129 (a key post-translational modification in disease), and enhances the formation of insoluble aggregates[@kim2024]. Furthermore, IL-1α-induced inflammation may act as a co-factor that facilitates the templated propagation of α-synuclein pathology from cell to cell, accelerating disease progression.
IL-1α is a potent activator of the [NLRP3 inflammasome](/entities/nlrp3-inflammasome) in microglia. While IL-1α itself is not processed by the inflammasome (unlike IL-1β), IL-1α signaling can prime (but not activate) the NLRP3 inflammasome by inducing pro-IL-1β transcription. A secondary trigger (e.g., ATP, nigericin, or α-synuclein fibrils) then activates the inflammasome, leading to caspase-1 activation and mature IL-1β release. This creates a cross-talk circuit between IL-1α and IL-1β that amplifies neuroinflammation in PD.
Elevated IL-1α in spinal cord tissue and CSF of ALS patients correlates with disease progression rate. In SOD1 transgenic mice (an ALS model), IL-1α is highly expressed in activated microglia in the spinal cord, and IL-1R1 deletion or blockade extends survival, suggesting IL-1α contributes to motor neuron death in ALS[@shaftel2023].
IL-1α promotes demyelination and enhances leukocyte trafficking into the CNS in multiple sclerosis. The cytokine drives Th17 cell differentiation and expansion, and IL-1R1 blockade is protective in experimental autoimmune encephalomyelitis (EAE), the mouse model of MS[@brough2022].
IL-1α is released immediately following TBI and serves as a predictive biomarker of outcome. Acute IL-1α levels in CSF shortly after injury correlate with lesion volume and clinical outcome at 6 months. Early IL-1R1 blockade (e.g., with anakinra) shows neuroprotective effects in both animal models and early clinical studies[@zhang2022].
IL-1α is elevated in FTD brain tissue, particularly in association with TDP-43 pathology. The inflammatory environment in FTD shares features with AD and PD neuroinflammation, suggesting common therapeutic targeting opportunities.
IL-1α is released by distinct mechanisms compared to other cytokines:
Cerebrospinal fluid IL-1α is emerging as a biomarker of in-brain neuroinflammation:
Peripheral blood IL-1α is less informative than CSF because of confounding systemic inflammation. However, in combination with other markers (IL-6, TNF-α, GFAP, neurofilament light chain), IL-1α contributes to a peripheral inflammatory signature that correlates with brain neuroinflammation burden.
Beyond direct IL-1R1 antagonism, several strategies target the IL-1α pathway:
| Strategy | Agent | Mechanism | Status |
|----------|-------|-----------|--------|
| IL-1RA | Anakinra | Competitive IL-1R1 antagonist | Phase 2 AD/PD trials |
| IL-1R1 mAb | AMG 108 / MEDI8962 | Neutralizing IL-1R1 | Phase 1 complete |
| IL-1α mAb | 4E12 | Neutralizing IL-1α specifically | Preclinical |
| ASC inhibitors | MCC950 (NLRP3) | Blocks IL-1β production (limits IL-1α cross-talk) | Preclinical |
| Calpain inhibitors | MDL-28170 | Blocks pro-IL-1α → mature IL-1α cleavage | Preclinical |
| BBB-penetrant IL-1RA | XBX-AD-01 | Engineered BBB-penetrant IL-1RA | Preclinical |
| Gene therapy | AAV-IL-1RA | CNS-directed IL-1RA expression | Preclinical |