| IL17A |
|---|
| Full Name | Interleukin 17A |
| Symbol | IL17A |
| Chromosome | 6p12.2 |
| NCBI Gene ID | [3605](https://www.ncbi.nlm.nih.gov/gene/3605) |
| Ensembl ID | ENSG00000112116 |
| OMIM ID | 603250 |
| UniProt ID | [Q16552](https://www.uniprot.org/uniprot/Q16552) |
| Protein Size | 155 amino acids (homodimer) |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [Multiple Sclerosis](/diseases/multiple-sclerosis), Stroke |
IL17A (Interleukin-17A) is the founding member of the IL-17 cytokine family, encoded by the IL17A gene on chromosome 6p12.2. It is a 155-amino acid secreted glycoprotein that forms disulfide-linked homodimers. IL-17A is produced primarily by Th17 cells (a distinct CD4+ T helper subset), as well as by innate immune cells including gamma-delta (γδ) T cells, innate lymphoid cells type 3 (ILC3s), natural killer T (NKT) cells, and neutrophils. IL-17A is a potent pro-inflammatory cytokine that plays critical roles in host defense against extracellular bacteria and fungi, but is also central to the pathogenesis of autoimmune diseases and has been increasingly recognized as a contributor to neuroinflammation in neurodegenerative diseases [@kolls2012][@linares2013].
¶ Receptor and Signaling
IL-17A signals through a heterodimeric receptor complex:
- IL17RA (IL-17 Receptor A): ubiquitously expressed, forms the signaling subunit
- IL17RC: co-receptor, especially highly expressed in non-immune cells including neurons and glia
The IL-17A/RA complex recruits the adaptor protein ACT1 (encoded by TNF receptor-associated factor 3 interacting protein 2, TRAF3IP2), which activates downstream signaling pathways:
- NF-κB pathway: Classical pro-inflammatory signaling via IKK complex activation
- MAPK pathways: C/EBPβ, C/EBPδ, and AP-1 family transcription factors
- C/EBP activation: Gene expression programs for chemokines and inflammatory mediators
The downstream effects include:
| Target Type |
Examples |
Function |
| Pro-inflammatory cytokines |
IL-6, TNF-α, IL-1β |
Amplify inflammation |
| Chemokines |
CXCL1, CXCL8, CCL20 |
Recruit neutrophils |
| Antimicrobial peptides |
β-defensins, S100A8/A9 |
Host defense |
| MMPs |
MMP1, MMP3, MMP9 |
Tissue remodeling |
- Th17 cells: CD4+ T helper cells differentiated under TGF-β, IL-6, IL-21, and IL-23
- γδ T cells: Innate-like T cells producing IL-17A rapidly in response to stress
- ILC3s: Innate lymphoid cells providing early IL-17A response
- Neutrophils: Can produce IL-17A in chronic inflammatory settings
IL-17A levels are elevated in the cerebrospinal fluid and brain tissue of Alzheimer's Disease patients. Key contributions include:
- Neuroinflammation amplification: IL-17A promotes chronic inflammation in the brain microenvironment, activating microglia and astrocytes
- Blood-brain barrier disruption: IL-17A increases BBB permeability, allowing peripheral immune cell infiltration
- Synapse toxicity: IL-17A signaling in neurons can lead to synaptic dysfunction and loss
- Aβ interaction: IL-17A may synergize with amyloid-β to drive microglial activation and neurotoxicity [@chai2023][@wu2017]
In Parkinson's Disease, IL-17A contributes to dopaminergic neuron death through multiple mechanisms:
- Direct toxicity to dopaminergic neurons: IL-17A activates apoptotic pathways in substantia nigra neurons
- Microglial activation: IL-17A is a potent activator of pro-inflammatory microglia (M1 phenotype)
- Th17 infiltration: Peripheral Th17 cells may cross the BBB and exacerbate nigral inflammation
- MPTP model evidence: In the MPTP mouse model of PD, IL-17A neutralization protects dopaminergic neurons and improves motor function [@yang2018][@yang2015]
IL-17A is central to Multiple Sclerosis pathogenesis:
- EAE induction: IL-17A is critical for experimental autoimmune encephalomyelitis (EAE), the mouse model of MS
- Demyelination: IL-17A drives oligodendrocyte death and myelin damage
- Clinical trials: Secukinumab (anti-IL-17A) showed efficacy in MS Phase II trials, with further studies ongoing [@bielekova2020]
¶ Stroke and Ischemia
- Exacerbates ischemic injury: IL-17A levels rise rapidly after stroke and contribute to secondary neuronal damage
- Post-stroke inflammation: IL-17A from γδ T cells drives early inflammatory response that worsens outcomes
| Drug |
Target |
Indication |
Notes |
| Secukinumab |
IL-17A |
Psoriasis, Psoriatic Arthritis, Ankylosing Spondylitis |
Approved; MS trials ongoing |
| Ixekizumab |
IL-17A |
Psoriasis, PsA |
Approved |
| Bimekizumab |
IL-17A/F |
Psoriasis |
Dual IL-17A/F inhibition |
- Secukinumab in MS: Phase II trials showed reduced MRI lesions and clinical progression
- Rinvoq (JAK inhibitor): Indirectly reduces IL-17A signaling via JAK-STAT pathway; approved for inflammatory diseases
- Infection risk: IL-17A blockade increases susceptibility to extracellular bacterial and fungal infections
- Mucosal immunity: Disruption of IL-17A-dependent host defense at barrier surfaces
- CNS delivery: Ensuring adequate CNS penetration for brain-resident inflammation