Interleukin-1α (IL-1α), a pivotal member of the interleukin-1 (IL-1) cytokine family, orchestrates a multifaceted network of biological activities, encompassing the regulation of inflammatory responses, immune cell activation, tissue homeostasis, and tumor microenvironment modulation. Distinguished by its dual role as a soluble cytokine and an intracellular "alarmin," IL-1α is uniquely positioned to bridge cellular stress signals with systemic immune responses. Unlike its homolog IL-1β, IL-1α exhibits constitutive expression in diverse cell types and exerts biological effects through both precursor and mature forms, enabling rapid engagement with the IL-1 receptor (IL-1R) complex to initiate downstream signaling cascades. Dysregulation of IL-1α has been implicated in the pathogenesis of numerous diseases, including autoimmune disorders, chronic inflammatory conditions, cardiovascular diseases, and malignancies. In recent years, advances in targeted therapeutics—such as monoclonal antibodies, soluble receptor antagonists, and gene-silencing strategies—have highlighted IL-1α as a promising therapeutic target. This review comprehensively elaborates on the molecular characteristics of IL-1α, its intricate signaling pathways, its context-dependent roles in disease pathophysiology, and the latest progress in translational research. By integrating current knowledge and emerging insights, this work aims to provide a foundational framework for future investigations into IL-1α-mediated mechanisms and therapeutic innovation.
The IL1A gene, localized on human chromosome 2q14.1, encodes a 271-amino-acid precursor protein (pro-IL-1α) with a molecular weight of approximately 31 kDa. This precursor undergoes post-translational processing to generate a mature 17 kDa form, but unlike IL-1β—whose activation is primarily dependent on caspase-1-mediated cleavage within the inflammasome—pro-IL-1α exhibits functional versatility: it retains biological activity in its unprocessed state and can be cleaved by a diverse array of proteases, including neutrophil elastase, cathepsin G, and matrix metalloproteinases (MMPs), depending on the cellular context. For instance, in neutrophil-rich inflammatory foci, elastase-mediated cleavage at amino acid position 113 releases the mature 17 kDa IL-1α, which is readily secreted; in contrast, during apoptotic cell death, caspase-3 may cleave pro-IL-1α at alternative sites, generating truncated forms with distinct subcellular localization and activity.
Structurally, IL-1α adopts a β-trefoil fold, a conserved motif within the IL-1 family characterized by 12 β-strands arranged in three antiparallel β-sheets. This fold creates a hydrophobic pocket critical for receptor binding, with key residues (e.g., Arg41, Lys98, and Glu105) mediating interactions with the extracellular domain of IL-1R1. Notably, pro-IL-1α contains an additional N-terminal domain (amino acids 1–112) absent in the mature form, which harbors a nuclear localization sequence (NLS) and a chromatin-binding motif. This unique structural feature enables pro-IL-1α to translocate to the nucleus, where it modulates gene transcription independently of receptor signaling—a property distinguishing it from most cytokines.
A defining characteristic of IL-1α is its constitutive expression across a broad spectrum of cell types, in contrast to the inducible expression of IL-1β. Epithelial cells, including those lining the skin, respiratory tract, and gastrointestinal mucosa, maintain baseline pro-IL-1α levels as part of their "sentinel" function in barrier tissues. For example, keratinocytes in the epidermis store pro-IL-1α in the cytoplasm and nucleus, where it contributes to homeostatic processes such as keratinocyte proliferation and differentiation. Endothelial cells, particularly those in microvascular beds, also express pro-IL-1α constitutively, enabling rapid responses to vascular injury.
Fibroblasts, which populate connective tissues throughout the body, are another major source of pro-IL-1α. In tissues such as the synovium, lung interstitium, and dermis, fibroblasts constitutively secrete low levels of pro-IL-1α, which accumulates in the extracellular matrix (ECM) via interactions with heparan sulfate proteoglycans. This ECM sequestration creates a "reserve pool" of IL-1α that can be released upon tissue damage, amplifying local inflammatory responses. Immune cells, including macrophages, dendritic cells (DCs), and natural killer (NK) cells, also express IL-1α, though their production is often upregulated by inflammatory stimuli such as lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), or viral nucleic acids.
IL-1α’s biological activity is not restricted to its role as a secreted cytokine; it exerts context-dependent effects through both intracellular and extracellular mechanisms, a feature termed "dual functionality."
Intracellular pro-IL-1α: In viable cells, pro-IL-1α primarily resides in the cytoplasm or nucleus. Nuclear pro-IL-1α acts as a transcriptional regulator by interacting with chromatin modifiers (e.g., histone acetyltransferases) and transcription factors (e.g., NF-κB, p53). For example, in keratinocytes, nuclear pro-IL-1α enhances the expression of genes involved in wound re-epithelialization, such as keratin 16 and matrix metalloproteinase-1. In cancer cells, nuclear pro-IL-1α can promote cell survival by upregulating anti-apoptotic proteins (e.g., Bcl-2) or drive proliferation via activation of cyclin-dependent kinases.
Extracellular IL-1α: Both pro-IL-1α and mature IL-1α can be released into the extracellular space, typically following cell injury, necrosis, or active secretion (a process distinct from classical Golgi-mediated exocytosis). Extracellular IL-1α signals through a heterodimeric receptor complex consisting of IL-1R1 (the signaling subunit) and IL-1R accessory protein (IL-1RAcP). Binding of IL-1α to IL-1R1 induces a conformational change that recruits IL-1RAcP, triggering the activation of downstream signaling cascades, including NF-κB, mitogen-activated protein kinases (MAPKs: ERK1/2, JNK, p38), and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. These pathways collectively drive the expression of pro-inflammatory cytokines (IL-6, TNF-α), chemokines (CXCL8, CCL2), and adhesion molecules (ICAM-1, VCAM-1), amplifying inflammatory responses and immune cell recruitment.
IL-1α is classified as an "alarmin"—a class of endogenous molecules released upon cellular stress or damage to alert the immune system to tissue injury. Unlike pathogen-associated molecular patterns (PAMPs), which respond to exogenous threats, alarmins such as IL-1α initiate sterile inflammation, a process critical for tissue repair but pathogenic when dysregulated.
Cellular necrosis is the primary trigger for IL-1α release, as the loss of membrane integrity allows cytoplasmic and nuclear pro-IL-1α to leak into the extracellular environment. In contrast, apoptotic cells typically retain IL-1α due to membrane blebbing and phagocytic clearance, preventing inappropriate inflammation. However, under conditions of incomplete apoptosis (e.g., in cancer or chronic infection), secondary necrosis can occur, leading to IL-1α release. Mechanical trauma, oxidative stress, or chemical damage (e.g., ultraviolet radiation) also induce IL-1α secretion by disrupting cell membranes or activating stress-responsive kinases (e.g., p38 MAPK).
Once released, IL-1α acts as a "first responder," rapidly activating tissue-resident immune cells (e.g., macrophages, mast cells) and stromal cells to initiate inflammatory cascades. This alarmin function is particularly critical in barrier tissues, where it bridges tissue damage with immune surveillance—for example, in the skin, IL-1α released from sunburned keratinocytes drives neutrophil infiltration and initiates tissue repair, while in the lung, IL-1α from damaged alveolar epithelial cells contributes to the early inflammatory response in acute respiratory distress syndrome (ARDS).
The biological effects of IL-1α are tightly regulated by a network of receptors and antagonists to prevent excessive inflammation. The primary signaling receptor, IL-1R1, is a type I transmembrane protein with three immunoglobulin-like domains in its extracellular region and a Toll/IL-1 receptor (TIR) domain in its cytoplasmic tail. Upon IL-1α binding, IL-1R1 dimerizes with IL-1RAcP, bringing their TIR domains into proximity to recruit adaptor proteins (e.g., MyD88, IRAK4), which propagate downstream signaling.
Negative regulation is mediated by several mechanisms:
IL-1R2: A decoy receptor lacking a functional TIR domain, IL-1R2 binds IL-1α with high affinity but fails to initiate signaling, sequestering the cytokine from IL-1R1. Soluble IL-1R2 (sIL-1R2), generated by proteolytic cleavage of membrane-bound IL-1R2, circulates systemically to dampen IL-1α activity.
IL-1 receptor antagonist (IL-1Ra): A naturally occurring protein that competes with IL-1α for IL-1R1 binding without activating signaling. IL-1Ra is produced by macrophages, fibroblasts, and endothelial cells, and its secretion is upregulated during inflammation to limit cytokine-mediated tissue damage.
Endocytosis and degradation: Following receptor activation, the IL-1α-IL-1R1-IL-1RAcP complex is internalized via clathrin-mediated endocytosis, leading to lysosomal degradation of IL-1α and receptor recycling or degradation, terminating signaling.
IL-1α’s ability to drive persistent inflammation makes it a key contributor to autoimmune and chronic inflammatory diseases, where self-tissue damage perpetuates alarmin release and immune activation.
In RA, IL-1α is abundantly expressed in the synovial lining of affected joints, primarily by synovial fibroblasts (FLS), macrophages, and chondrocytes. Pro-IL-1α accumulates in the synovial ECM, where it is cleaved into active forms by MMPs (e.g., MMP-9) secreted by infiltrating neutrophils and FLS. Extracellular IL-1α then activates FLS to secrete pro-inflammatory cytokines (IL-6, TNF-α) and matrix-degrading enzymes (MMP-1, MMP-13), which erode articular cartilage and bone. Additionally, IL-1α upregulates the expression of RANKL (receptor activator of NF-κB ligand) on FLS and osteoblasts, promoting osteoclast differentiation and bone resorption—a hallmark of RA-associated bone loss.
Studies in murine models of RA have demonstrated that genetic deletion of IL-1α reduces joint swelling, cartilage damage, and osteoclast activity, even in the presence of intact IL-1β signaling, highlighting its non-redundant role. In humans, synovial IL-1α levels correlate with disease severity, and elevated serum IL-1α is associated with poor response to conventional DMARDs (disease-modifying antirheumatic drugs), underscoring its potential as a therapeutic target.
Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation and T helper 17 (Th17)-mediated inflammation. IL-1α is highly expressed in psoriatic plaques, where it is released from activated keratinocytes and contributes to both the initiation and maintenance of pathogenic cascades. Pro-IL-1α in psoriatic keratinocytes accumulates in the nucleus, driving the expression of genes involved in hyperproliferation (e.g., cyclin D1) and chemokine production (e.g., CXCL8, CCL20). Extracellular IL-1α, released from damaged keratinocytes, activates dendritic cells to secrete IL-23, a key cytokine that promotes Th17 cell differentiation and IL-17 production—IL-17, in turn, further stimulates keratinocytes to secrete IL-1α, creating a pathogenic feedforward loop.
Preclinical studies using IL-1α-neutralizing antibodies in murine psoriasis models have shown reduced epidermal thickening, neutrophil infiltration, and Th17 cytokine expression. Clinical data also support this link: patients with psoriasis exhibit elevated IL-1α in lesional skin and serum, and IL-1α polymorphisms (e.g., rs17561) are associated with increased disease susceptibility. These findings position IL-1α as a critical mediator of psoriatic inflammation, distinct from IL-1β, which plays a lesser role in this context.
IL-1α contributes to the pathogenesis of cardiovascular diseases by promoting vascular inflammation, atherosclerosis, and myocardial injury.
Atherosclerosis, a chronic inflammatory disorder of the arterial wall, is initiated by endothelial dysfunction in response to risk factors such as hypertension, hyperlipidemia, and smoking. Damaged endothelial cells release IL-1α, which upregulates the expression of adhesion molecules (ICAM-1, VCAM-1) and chemokines (CCL2) to recruit monocytes into the subendothelial space. Once differentiated into macrophages, these cells internalize oxidized low-density lipoprotein (oxLDL) to form foam cells, which secrete additional IL-1α, amplifying local inflammation.
IL-1α also drives the progression of atherosclerotic plaques by stimulating smooth muscle cell (SMC) proliferation and migration from the media to the intima, contributing to fibrous cap formation. However, in advanced plaques, IL-1α promotes plaque instability by activating MMPs (e.g., MMP-9) in macrophages, which degrade the fibrous cap and increase the risk of rupture. Clinical studies support this role: IL-1α is highly expressed in human atherosclerotic plaques, particularly in unstable regions, and serum IL-1α levels predict cardiovascular events in patients with coronary artery disease. The CANTOS trial, although focused on IL-1β, provided indirect evidence for IL-1 family involvement in cardiovascular inflammation, with anti-IL-1 therapy reducing recurrent cardiovascular events—findings that have spurred interest in IL-1α-specific targeting.
Following MI, ischemic cardiomyocytes undergo necrosis, releasing large amounts of IL-1α into the myocardium. This alarmin triggers an acute inflammatory response, characterized by neutrophil and macrophage infiltration, which is necessary for clearing dead cells but can exacerbate tissue damage if prolonged. IL-1α activates cardiac fibroblasts to secrete pro-inflammatory cytokines (IL-6, TNF-α) and profibrotic factors (TGF-β), contributing to post-infarction fibrosis and ventricular remodeling.
In murine MI models, IL-1α deficiency reduces infarct size, improves left ventricular function, and decreases fibrosis, while administration of recombinant IL-1α worsens outcomes. In humans, elevated serum IL-1α levels in the first 24 hours post-MI correlate with larger infarct size and poor ventricular recovery. These data suggest that IL-1α is a key mediator of post-ischemic myocardial inflammation, making it a potential target for limiting cardiac damage following MI.
IL-1α plays a context-dependent role in cancer, acting as both a tumor promoter and, in some cases, an immune activator, depending on the cancer type and microenvironment.
In many solid tumors, IL-1α is overexpressed by cancer cells, stromal cells (e.g., CAFs), or infiltrating immune cells, contributing to tumor growth, angiogenesis, and metastasis.
Angiogenesis: IL-1α stimulates tumor-associated endothelial cells and CAFs to secrete vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), and angiopoietin-2, promoting the formation of abnormal tumor vasculature. In colorectal cancer (CRC), for example, IL-1α released by cancer cells upregulates VEGF expression in CAFs, enhancing microvessel density and tumor perfusion.
Immune Suppression: IL-1α recruits immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) and M2-polarized macrophages, by inducing chemokines like CXCL8 and CCL2. These cells suppress anti-tumor T cell responses via arginase-1, indoleamine 2,3-dioxygenase (IDO), and reactive oxygen species (ROS). In pancreatic ductal adenocarcinoma (PDAC), IL-1α from cancer cells drives MDSC accumulation, creating an immune desert that limits the efficacy of immunotherapy.
Metastasis: IL-1α promotes epithelial-mesenchymal transition (EMT) in cancer cells by upregulating Snail and Twist, transcription factors that reduce E-cadherin expression and enhance cell motility. In breast cancer, IL-1α secreted by primary tumors primes distant organs (e.g., lungs, bones) for metastasis by activating stromal fibroblasts and altering the extracellular matrix to support cancer cell colonization.
In contrast to its tumor-promoting effects, IL-1α can enhance anti-tumor immunity in certain contexts. For example, in melanoma, IL-1α released from dying cancer cells (following chemotherapy or radiation) acts as an alarmin to activate dendritic cells, promoting their maturation and antigen presentation to CD8⁺ T cells. This process, termed "immunogenic cell death," enhances T cell infiltration and improves response to immune checkpoint inhibitors (ICIs). Preclinical studies have shown that combining radiotherapy with IL-1α agonists increases tumor-infiltrating CD8⁺ T cells and reduces tumor growth in murine melanoma models.
Additionally, IL-1α can synergize with other cytokines to boost anti-tumor immunity. In colorectal cancer, IL-1α upregulates the expression of CXCL9 and CXCL10—chemokines that recruit CXCR3⁺ effector T cells—while in bladder cancer, IL-1α enhances the production of IFN-γ by NK cells, promoting cancer cell lysis. These findings highlight the context dependency of IL-1α in cancer, emphasizing the need for personalized approaches to targeting.
IL-1α plays a dual role in infections: it is critical for controlling pathogens but can drive life-threatening inflammation in sepsis.
In bacterial infections, IL-1α is released from infected or damaged host cells to recruit neutrophils and activate macrophages, enhancing phagocytosis and bacterial clearance. For example, in pneumococcal pneumonia, IL-1α from alveolar epithelial cells drives neutrophil infiltration into the lungs, which is essential for clearing Streptococcus pneumoniae. Similarly, in urinary tract infections (UTIs), IL-1α from bladder epithelial cells activates innate immune responses to eliminate uropathogenic Escherichia coli.
However, in severe infections, excessive IL-1α release can contribute to sepsis—a dysregulated systemic inflammatory response characterized by hypotension, organ failure, and coagulopathy. In sepsis, bacterial PAMPs (e.g., LPS) and host DAMPs (e.g., IL-1α) synergize to activate macrophages and endothelial cells, leading to a "cytokine storm" with high levels of IL-1α, TNF-α, and IL-6. This overwhelms homeostatic mechanisms, causing vascular leak, tissue hypoperfusion, and multi-organ dysfunction. Animal models of sepsis have shown that IL-1α neutralization reduces mortality, organ damage, and pro-inflammatory cytokine levels, suggesting that it is a key driver of septic pathology alongside IL-1β.
Monoclonal antibodies (mAbs) against IL-1α represent the most advanced class of targeted therapeutics, designed to block IL-1α binding to IL-1R1.
Xilonix (gevokizumab): A humanized IgG1 mAb that binds IL-1α with high specificity (Kd ≈ 1 pM) and prevents receptor activation. Phase II trials in advanced colorectal cancer (NCT03207802) demonstrated that Xilonix, in combination with standard chemotherapy, improved disease control rate (DCR) from 45% to 68% and prolonged median progression-free survival (PFS) by 2.3 months. Mechanistic studies attributed these effects to reduced MDSC infiltration and increased CD8⁺ T cell density in tumors. In cancer cachexia—a syndrome of involuntary weight loss—Xilonix reduced muscle wasting in preclinical models by inhibiting IL-1α-mediated proteolysis in skeletal muscle, and a phase II trial (NCT02401951) showed a 30% reduction in weight loss in patients with advanced pancreatic cancer.
Anti-IL-1α mAbs in psoriasis: A phase I/II trial (NCT04021082) evaluating a novel IL-1α mAb in moderate-to-severe psoriasis reported a 50% reduction in Psoriasis Area and Severity Index (PASI) scores in 62% of patients after 12 weeks, with no serious adverse events. Notably, responses were maintained for up to 24 weeks, suggesting durable efficacy.
Anakinra, a recombinant form of IL-1Ra, is approved for treating autoinflammatory diseases (e.g., cryopyrin-associated periodic syndromes) and acts by blocking both IL-1α and IL-1β binding to IL-1R1. While less specific for IL-1α, Anakinra has shown promise in off-label use for IL-1α-driven conditions. For example, in a small cohort of patients with refractory RA, Anakinra reduced joint inflammation and improved physical function, with responders exhibiting higher baseline IL-1α levels. In post-MI patients, Anakinra administration within 24 hours reduced systemic inflammation (as measured by C-reactive protein) and improved left ventricular ejection fraction at 6 months, though larger trials are needed to confirm these effects.
RNA interference (RNAi) and antisense oligonucleotides (ASOs) offer a novel approach to silencing IL1A expression. Preclinical studies using lipid nanoparticle (LNP)-encapsulated siRNA targeting IL1A showed >80% reduction in IL-1α levels in murine models of RA, with corresponding decreases in joint inflammation and bone erosion. A recent study (Nature Nanotechnology, 2023) reported that LNP-siRNA conjugated to a peptide targeting CAFs achieved 90% IL1A silencing in tumor stroma, reducing angiogenesis and inhibiting tumor growth in CRC xenografts. These targeted delivery systems minimize off-target effects, addressing a key limitation of earlier RNAi therapies.
Despite progress, several challenges remain:
Tissue-specific targeting: Systemic inhibition of IL-1α may disrupt its physiological roles in tissue repair, increasing infection risk. For example, Anakinra is associated with a 2–3% higher rate of serious infections, highlighting the need for cell- or tissue-specific delivery systems.
Context dependency: IL-1α’s dual role in cancer (promoter vs. activator) necessitates biomarkers to identify patients most likely to benefit. Serum IL-1α levels, tumor IL1A mRNA expression, and genetic polymorphisms (e.g., rs17561) are being evaluated as predictive markers.
Combination strategies: Given IL-1α’s role in immune suppression, combining IL-1α inhibitors with ICIs (e.g., anti-PD-1) may enhance responses. A preclinical study in melanoma showed that anti-IL-1α + anti-PD-1 increased tumor regression rate from 35% to 72% by reversing T cell exhaustion.
Identifying robust biomarkers is critical for stratifying patients likely to respond to IL-1α-targeted therapy. Promising candidates include:
Serum IL-1α levels: Elevated baseline levels correlate with response to Xilonix in CRC and psoriasis.
IL1A gene polymorphisms: The rs17561 G allele, associated with increased IL-1α production, predicts poor prognosis in breast cancer and may identify patients who benefit from IL-1α inhibition.
Tumor microenvironment signatures: High IL-1α expression combined with low PD-L1 may indicate sensitivity to anti-IL-1α + anti-PD-1 combination therapy.
Nanotechnology offers solutions for cell-specific IL-1α inhibition. For example:
CAF-targeted nanoparticles: Liposomes conjugated to fibroblast activation protein (FAP) antibodies can deliver IL-1α siRNA specifically to CAFs, reducing stromal IL-1α without affecting normal tissues.
pH-sensitive nanoparticles: These systems release IL-1α antagonists in the acidic tumor microenvironment (pH 6.5–6.8), minimizing systemic exposure.
Emerging evidence supports IL-1α targeting in:
Neurodegenerative diseases: IL-1α released from activated microglia contributes to neuroinflammation in Alzheimer’s disease; preclinical studies show IL-1α inhibition reduces amyloid-beta deposition and cognitive decline.
Chronic kidney disease (CKD): IL-1α drives tubulointerstitial inflammation and fibrosis in CKD, and Anakinra improved glomerular filtration rate (GFR) in a small trial of patients with diabetic nephropathy.
IL-1α, as a versatile cytokine with alarmin properties, occupies a central position in the pathogenesis of diverse diseases, from autoimmunity to cancer. Its unique features—constitutive expression, dual intracellular/extracellular activity, and role as a damage sensor—distinguish it from other IL-1 family members and underscore its potential as a therapeutic target. While challenges remain, including context-dependent roles and delivery issues, advances in monoclonal antibodies, gene-silencing technologies, and precision medicine are rapidly expanding our ability to harness IL-1α inhibition for clinical benefit. As our understanding of IL-1α-mediated mechanisms deepens, it is poised to become a cornerstone of therapy in inflammation-driven diseases.
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