Noncanonical Regulation of ACKR3/CXCR7 on Lipid Mediators in Immunothrombotic Platelet Response following FcγRIIa Stimulation

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Introduction: FcγRIIA mediated platelet activation drives immunothrombosis as in heparin induced thrombocytopenia-(HIT), acute infections (e.g. SARS-CoV2) and is associated with hypercoagulation. Although anticoagulants are preferred choice of treatment, effective antiplatelet strategies are still under validation. Current investigation explores the involvement of lipid mediators and the therapeutic potential of CXCR7 in modulating immunothrombotic platelet response. Method: Lipidomics analysis was done by UHPLC-QTOF-MS/MS and micro-UHPLC-ESI-QTrap-MS/MS, platelet degranulation, α IIb β III -integrin activation, phosphatidylserine exposure, platelet-neutrophil aggregate formation by flow cytometry, thrombin generation by calibrated automated thrombinoscopy, phosphorylation of SykTyr 525/526 , SykTyr 323 by immunoblot analysis. Results: IgGs from HIT, severe and non-severe COVID-19 patients substantially induced platelet degranulation, α IIb β III -integrin activation, like collagen related peptide (CRP), which were significantly countered by a pharmacological CXCR7-agonist. Moreover, active-CD11b surface expression on neutrophils and formation of thrombo-inflammatory platelet-neutrophil aggregates induced by IgGs and CRP were also decreased. We detected enhanced platelet procoagulant activity in terms of thrombogenic phospholipid phosphatidylserine exposure and consequently procoagulant platelet assisted thrombin generation in platelet rich plasma upon treatment with IgGs and CRP, that were significantly reduced by CXCR7-agonist. Changes to the platelet lipidome (e.g. generation of oxylipins) induced by IgGs were distinctively different from those induced by CRP. Moreover, generation of thrombo-inflammatory lipids through platelet COX-1 (TxA 2 ), 12-LOX (12-HETE) and leukocyte specific 5-LOX (5-HETE), 15-LOX (15-HETE) were triggered upon treatment with HIT + sera and downregulated by CXCR7-agonist. Presence of CXCR7-agonist also intercepted transcellular lipid metabolism between platelet and leukocytes (5,12-diHETE, 12,20-diHETE, 13-HODE, 9-HODE). Like 12-LOX, Syk is a major player downstream of FcγRIIA- induced platelet activatory signalling, and therefore considered a potential therapeutic target. CXCR7-agonist countered Syk Tyr525/526 , Syk Tyr323 phosphorylation triggered by IgGs from HIT and COVID-19 patients, also following CRP stimulation. Conclusion: Considering the dual regulatory impact on pharmacological CXCR7-agonist on 12-LOX and Syk activities, therapeutic targeting of CXCR7 may modulate immunothrombotic complications arising from FcγRIIA induced platelet activation. Publication History Article published online: 13 February 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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