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Peer-reviewedCC BY 4.0Frontiers in Immunology

Targeting P2Y12 limits TH17 accumulation in the CNS and reduces EAE progression

  • Niklas Huntemann1,2
  • Lara-Maria Preuth1,2
  • Thorsten F. Krug1,3
  • Anna Vogelsang1
  • Linda Groeneweg1,4
  • Paul Disse2
  • Rajeevan Narayanan Therpurakal1,2
  • Alexander Zarbock5
  • Bernhard Nieswandt6
  • Kerstin Göbel1
  • Harald F. Langer7
  • Tobias Ruck8,9
4 more authors
  • Antje Schmidt-Pogoda1
  • Amin Polzin10,11
  • Susann Eichler1,12,13
  • Sven G. Meuth1,2
13 affiliations
  1. 1Department of Neurology, University Hospital Münster
  2. 2Department of Neurology, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf
  3. 3Department of Radiology, Clemenshospital GmbH Münster
  4. 4Institute of Immunology, University of Münster
  5. 5Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Münster
  6. 6Rudolf Virchow Center, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, University of Würzburg
  7. 7Department of Medicine, Division of Cardiology, Angiology, Hemostasis, and Medical Intensive Care, Medical Faculty Mannheim, University of Heidelberg
  8. 8Department of Neurology, BG University Hospital Bergmannsheil, Ruhr University Bochum
  9. 9BG University Hospital Bergmannsheil, Heimer Institute for Muscle Research
  10. 10Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Düsseldorf
  11. 11Cardiovascular Research Institute Düsseldorf (CARID)
  12. 12Institute for Laboratory Medicine, Microbiology and Clinical Pathobiochemistry, Bielefeld University, Medical School and University Medical Center OWL - Campus Klinikum Lippe
  13. 13Department of Science and Academic Medicine, Bielefeld University, Medical School and University Medical Center OWL - Campus Klinikum Lippe
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Abstract

Platelets are increasingly recognized as active amplifiers of neuroinflammation in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). P2Y12 is an essential ADP receptor that regulates platelet activation and is upregulated in neuroinflammatory lesions. However, its contribution across different effector populations and therapeutic potential in autoimmune diseases of the central nervous system (CNS) remain incompletely defined. Therefore, we characterized P2ry12 expression across different immune and CNS-resident effector populations involved in EAE. To define P2Y12-dependent mechanisms in autoimmune neuroinflammation, we targeted the P2Y12 receptor both genetically and pharmacologically in MOG35–55-induced EAE and monitored disease course and immunopathology. The neuroinflammatory response was profiled by flow cytometry, histology, and cytokine analyses. Pharmacological inhibition with elinogrel or clopidogrel was evaluated in prophylactic and therapeutic treatment regimens. Additionally, prophylactic elinogrel treatment was combined with antibody-mediated platelet depletion during the effector phase of EAE to define the contribution of platelets to the observed effects. Among the immune and CNS-resident effector populations examined, platelets exhibited the highest abundance of P2ry12 transcripts, and platelet P2ry12 expression increased following EAE induction. Consistent with a proinflammatory role of the P2Y12 receptor in CNS autoimmunity, its genetic deficiency was associated with decreased disease progression, as indicated by lower peak and cumulative scores, while disease onset remained unchanged compared to wild-type mice. Pharmacological inhibition of the P2Y12 receptor reproduced this protective effect. Importantly, treatment with elinogrel did not affect the number of infiltrated platelets, but markedly reduced cellular infiltration and demyelination. Furthermore, the protective effect was associated with a significant reduction in infiltrating CD4+ T cells, particularly pro-inflammatory T helper 17 (TH17) cells. Of note, elinogrel provided no additional benefit beyond platelet depletion, a finding compatible with a platelet-mediated contribution to the observed effect. Clopidogrel, another P2Y12 inhibitor, similarly reduced disease severity when administered prophylactically. Of note, both elinogrel and clopidogrel remained effective when treatment was initiated after clinical onset. These data identify platelet-associated P2Y12 signaling as a functionally relevant amplifier of EAE pathology. P2Y12 blockade limits CNS immune infiltration and neuroinflammation-induced tissue injury, exerts an impact on the TH17 axis, and retains efficacy when administered therapeutically. Collectively, these findings support P2Y12 as a mechanistically grounded and translationally relevant target in CNS autoimmunity.

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Cite

BibTeXRIS
BibTeX
@article{huntemann2026targeting,
  title = {{Targeting P2Y12 limits TH17 accumulation in the CNS and reduces EAE progression}},
  author = {Niklas Huntemann and Lara-Maria Preuth and Thorsten F. Krug and Anna Vogelsang and Linda Groeneweg and Paul Disse and Rajeevan Narayanan Therpurakal and Alexander Zarbock and Bernhard Nieswandt and Kerstin Göbel and Harald F. Langer and Tobias Ruck and Antje Schmidt-Pogoda and Amin Polzin and Susann Eichler and Sven G. Meuth},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1946414},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1946414/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Targeting P2Y12 limits TH17 accumulation in the CNS and reduces EAE progression
AU  - Niklas Huntemann
AU  - Lara-Maria Preuth
AU  - Thorsten F. Krug
AU  - Anna Vogelsang
AU  - Linda Groeneweg
AU  - Paul Disse
AU  - Rajeevan Narayanan Therpurakal
AU  - Alexander Zarbock
AU  - Bernhard Nieswandt
AU  - Kerstin Göbel
AU  - Harald F. Langer
AU  - Tobias Ruck
AU  - Antje Schmidt-Pogoda
AU  - Amin Polzin
AU  - Susann Eichler
AU  - Sven G. Meuth
PY  - 2026
DA  - 2026/10/21
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1946414
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1946414/full
AB  - Platelets are increasingly recognized as active amplifiers of neuroinflammation in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). P2Y12 is an essential ADP receptor that regulates platelet activation and is upregulated in neuroinflammatory lesions. However, its contribution across different effector populations and therapeutic potential in autoimmune diseases of the central nervous system (CNS) remain incompletely defined. Therefore, we characterized P2ry12 expression across different immune and CNS-resident effector populations involved in EAE. To define P2Y12-dependent mechanisms in autoimmune neuroinflammation, we targeted the P2Y12 receptor both genetically and pharmacologically in MOG35–55-induced EAE and monitored disease course and immunopathology. The neuroinflammatory response was profiled by flow cytometry, histology, and cytokine analyses. Pharmacological inhibition with elinogrel or clopidogrel was evaluated in prophylactic and therapeutic treatment regimens. Additionally, prophylactic elinogrel treatment was combined with antibody-mediated platelet depletion during the effector phase of EAE to define the contribution of platelets to the observed effects. Among the immune and CNS-resident effector populations examined, platelets exhibited the highest abundance of P2ry12 transcripts, and platelet P2ry12 expression increased following EAE induction. Consistent with a proinflammatory role of the P2Y12 receptor in CNS autoimmunity, its genetic deficiency was associated with decreased disease progression, as indicated by lower peak and cumulative scores, while disease onset remained unchanged compared to wild-type mice. Pharmacological inhibition of the P2Y12 receptor reproduced this protective effect. Importantly, treatment with elinogrel did not affect the number of infiltrated platelets, but markedly reduced cellular infiltration and demyelination. Furthermore, the protective effect was associated with a significant reduction in infiltrating CD4+ T cells, particularly pro-inflammatory T helper 17 (TH17) cells. Of note, elinogrel provided no additional benefit beyond platelet depletion, a finding compatible with a platelet-mediated contribution to the observed effect. Clopidogrel, another P2Y12 inhibitor, similarly reduced disease severity when administered prophylactically. Of note, both elinogrel and clopidogrel remained effective when treatment was initiated after clinical onset. These data identify platelet-associated P2Y12 signaling as a functionally relevant amplifier of EAE pathology. P2Y12 blockade limits CNS immune infiltration and neuroinflammation-induced tissue injury, exerts an impact on the TH17 axis, and retains efficacy when administered therapeutically. Collectively, these findings support P2Y12 as a mechanistically grounded and translationally relevant target in CNS autoimmunity.
SN  - 1664-3224
ER  -