Characterising the role of inflammatory lipids in regulating systemic inflammation in arthritis

Costa, Daniela ORCID: https://orcid.org/0000-0001-8821-5898 2022. Characterising the role of inflammatory lipids in regulating systemic inflammation in arthritis. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Rheumatoid arthritis (RA) is linked to an elevated risk of thrombotic events, however, the mechanisms behind this are so far unknown. The activity of coagulation factors requires a pro-coagulant membrane provided by aminophospholipids, including phosphatidylserine (PS). Alongside this, enzymatically oxidised phospholipids (eoxPLs), including hydroxyeicosatetraenoic acid–phospholipids (HETE-PLs) enhance coagulation by supporting PS-dependent binding and activity of coagulation factors. EoxPL levels are elevated in human thrombotic disorders, namely abdominal aortic aneurysm, and antiphospholipid syndrome. To determine whether eoxPLs are elevated in arthritis-associated coagulopathies, antigen-induced arthritis (AIA) was generated in WT, Il27ra-/- , Il6ra-/- and Il6-/- mice, which develop histological phenotypes similar to humans. WT and Il27ra-/- AIA mice showed elevated eoxPLs, primarily 12-HETE-PEs in whole blood cells, which included red blood cells, white blood cells and platelets. In addition, higher thrombin-antithrombin complexes (TAT) levels were observed in these mice. However, neither Il6ra-/- nor Il6-/- mice exhibited increased levels of TATs or eoxPLs during AIA development. These results suggest that IL6 plays a role in increased coagulation, which may be linked with eoxPL levels in whole blood cells. Furthermore, in Alox15-/- mice, levels of whole blood cell 12- HETE-PEs were similar to WT, indicative of platelet 12-LOX activity, therefore suggesting platelets as the primary source of these lipids in whole blood. Human RA was also studied, however, no significant difference in eoxPLs and aminophospholipid exposure was seen in platelets and white blood cells (WBCs). Nevertheless, thrombocytosis wasobserved in these patients, which may increase circulating eoxPLs and aminophospholipid levels. Furthermore, EV-containing plasma from RA patients displayed higher levels of eoxPLs and externalized aminophospholipids, as well as supporting more thrombin generation than EVs from healthy controls. Last, an increased plasma IgG immunological response was observed against oxPLs in these patients, especially towards 12-HETE-PE. Overall, these results indicate that eoxPLs are elevated in arthritis and may play a role in the increased coagulation observed in RA, and platelets (or platelet-derived EVs), are important players in the elevated systemic coagulation of this disease.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	24 February 2023
Last Modified:	21 Feb 2024 02:30
URI:	https://orca.cardiff.ac.uk/id/eprint/157195

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