Anti-inflammatory and immuno-metabolic effects of pinolenic acid in rheumatoid arthritis

Takala, Rabaa 2022. Anti-inflammatory and immuno-metabolic effects of pinolenic acid in rheumatoid arthritis. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Introduction: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that causes chronic joint inflammation. Cardiovascular disease (CVD) is the leading cause of death in patients with RA due to accelerated atherosclerosis. In addition, patients have a higher susceptibility to plaque instability and atherothrombosis. Monocytes and macrophages cause synovitis and produce pro-inflammatory cytokines. Despite the increasing number of new treatments, complete long-term disease remission is rarely achieved. Moreover, side effects and safety concerns lead to poor adherence. The American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) recommend consuming a healthy and balanced diet to reduce the risk of RA. However, there is no specific recommendation for a specific type of food due to limited scientific evidence. Previous research on omega (n)-3 and -6 polyunsaturated fatty acids (PUFAs) has demonstrated anti-inflammatory and anti-atherogenic properties. Preliminary studies on pinolenic acid (PNLA), which is one of the unusual PUFAs found in pine nuts, showed anti-inflammatory actions in cell lines and animal models, while patients’ samples have not been studied. This project aims to explore the therapeutic potential of PNLA in RA and atherosclerosis. Methods: The THP-1 cell line and primary culture of human macrophages were initially used, followed by peripheral blood (PB) samples from RA patients and healthy individuals (HIs). Release of IL-6, TNF-α and IL-1β after lipopolysaccharide stimulation (LPS) by monocytes and macrophages was measured intra-cellularly and in cell-free supernatants with or without PNLA treatment. RNA sequencing was used to assess the gene expression level of peripheral blood mononuclear cells (PBMCs) and purified monocytes. Bioinformatic analyses were used to explore the effects of PNLA on biological pathways. Results: Key pro-atherogenic processes were inhibited by PNLA in vitro and ex vivo. PNLA does not affect the viability or proliferation of the THP-1 cell line, primary culture of macrophages or PBMCs from RA patients or HCs. PNLA attenuated monocyte chemoattractant protein-1 (MCP-1) or CCL2-induced monocyte migration, reduced micropinocytosis, and oxidised low-density lipoprotein (ox-LDL) uptake by macrophages. Gene expression analysis revealed that PNLA attenuated several key pro-inflammatory genes and regulated metabolic genes and transcription factors. Several mitochondrial pathways, such as mitochondrial phosphorylation and mitochondrial dysfunction, were identified as being regulated by PNLA. PNLA also has protective effects as identified by canonical pathways and differentially expressed genes such as pyruvate dehydrogenase kinase-4 (PDK4), serine protease inhibitor-1 (SERPIN1), fructose bisphosphate-1 (FBP1), and single-immunoglobulin interleukin-1 receptor-related molecule (SIGIRR). MicroRNAs (miRNAs) were discovered to be regulated by PNLA, suggesting potential post-transcriptional regulation of the immune response that has not been described previously. Conclusion: PNLA has anti-inflammatory and metabolic effects in experimental and ex vivo studies in patients with RA. Dietary supplements with PNLA may be beneficial for articular and vascular diseases in patients with RA through their immuno-metabolic effects and can potentially augment current treatments. Therefore, PNLA is a promising dietary element for RA and atherosclerosis. These beneficial effects have been illustrated in this thesis, and the necessary functional studies and clinical trials to further complement this work have also been discussed.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	19 May 2023
Date of Acceptance:	19 May 2023
Last Modified:	06 Jan 2024 04:20
URI:	https://orca.cardiff.ac.uk/id/eprint/159696

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