Characterising the role of Galectin-9 in platelet activation and thrombo-inflammatory disease.

Zhi, Zhaogong ORCID: 0000-0003-0896-1677 (2024). Characterising the role of Galectin-9 in platelet activation and thrombo-inflammatory disease. University of Birmingham. Ph.D.

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Abstract

Thrombosis and inflammation are two interrelated processes (termed thrombo-inflammation) that contribute to various pathologies, including infection, cardiovascular disease, autoimmune disorders, and cancer. Platelets have been proposed to be a major cellular mediator in thrombo-inflammation. Several members of galectins (Gal-1, -3, -8), a family of carbohydrate-binding proteins with a broad range of immunomodulatory actions, have been reported to activate platelets. Galectin-9 (Gal-9), an immunoregulatory protein, is rapidly emerging as a key inflammatory mediator and biomarker in numerous inflammatory diseases. In this thesis, we investigated the role of Gal-9 as a novel ligand for platelet glycoprotein VI (GPVI), C-type lectin-like receptor-2 (CLEC-2) and scavenger receptor CD36.
We have shown that Gal-9 binds to recombinant GPVI and CD36 in vitro. Soluble Gal-9 stimulates aggregation in human and mouse washed platelets dose-dependently. Platelets from both species adhere and spread on immobilised Gal-9 and express P-selectin. Gal-9 competitively inhibited the binding of human recombinant D1 and D2 domains of GPVI to collagen. Gal-9 stimulated tyrosine phosphorylation of CLEC-2 and proteins known to lie downstream of GPVI and CLEC-2 including spleen tyrosine kinase (Syk) and linker of activated T cells (LAT) in human platelets. Murine platelets with CD36, CLEC-2 and GPVI deficiency exhibited significantly impaired aggregation in response to Gal-9 which was further abrogated in GPVI and CLEC-2-double-deficient platelets.
We also demonstrated that Gal-9 downregulated CD36 expression on human platelets but upregulated the expression of membrane-bound TLR2/6 and S100A8/A9. Transgenic mice with Gal-9 deficiency exhibited attenuated thrombus formation in models of laser-induced thrombosis and intra vena cava (IVC)-stenosis, but had normal platelet counts and responses to collagen, collagen-related peptide (CRP), thrombin were observed when compared to wild-type littermates.
In conclusion, we have identified Gal-9 as a novel platelet agonist that induces activation through interaction with GPVI, CLEC-2 and CD36. Gal-9 is capable of initiating both the pro-thrombotic and pro-inflammatory phenotypes of platelets in vitro and supporting thrombosis in the microcirculation in vivo.

Type of Work:	Thesis (Doctorates > Ph.D.)
Award Type:	Doctorates > Ph.D.
Supervisor(s):	Supervisor(s) Email ORCID Iqbal, Asif Jilani UNSPECIFIED orcid.org/0000-0002-3224-3651 Watson, Steve P. UNSPECIFIED orcid.org/0000-0002-7846-7423 Rainger, George E. UNSPECIFIED UNSPECIFIED
Licence:	All rights reserved
College/Faculty:	Colleges (former) > College of Medical & Dental Sciences
School or Department:	Institute of Cardiovascular Sciences
Funders:	None/not applicable
Subjects:	R Medicine > R Medicine (General)
URI:	http://etheses.bham.ac.uk/id/eprint/14631

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