Modulation of lipid mediator pathways by glucocorticoids and vitamin E derivatives as anti-inflammatory treatment strategies

Despite substantial progress in the treatment of acute and chronic inflammation, and extensive research efforts in this field, our understanding of the immune system remains incomplete. Furthermore, drastic changes in living standards and dietary habits have led to an increased prevalence of chronic inflammatory diseases, such as diabetes mellitus and autoimmune disorders. The primary objective of this thesis was to deepen the knowledge of immunological regulation focusing on inflammation-related lipid mediators (LMs) and to contribute to the development of future therapeutic strategies. This work focuses on the enzymes 15-lipoxygenases (LOXs), 5-LOX and microsomal prostaglandin E synthase-1 (mPGES-1), which catalyze the oxygenation of polyunsaturated fatty acids, generating metabolites that play a critical role in modulating immune responses. Treatment with the glucocorticoid dexamethasone (Dex) led to a substantial alteration in the LM profile of M1-like and M2-like macrophages, shifting the profile to 15-monohydroxylated products while the levels of specialized pro-resolving mediators, typically produced by 15-LOX-1, were reduced. ALOX15B was upregulated in M1Dex and M2Dex, whereas ALOX15 was only minimally expressed in M2Dex. This differential expression pattern was confirmed at the protein level and in ex vivo samples from COVID-19 patients. Mechanistically, the glucocorticoid receptor was involved, with recruitment to intron 3 of ALOX15B. Functional studies showed that 15-LOX-2 did not enhance phagocytic activity and did not affect mitochondrial membrane potential. Also, structural optimization of semi-synthetic vitamin E derivatives identified key features for potent dual inhibition of 5-LOX and mPGES-1. In summary, this thesis elucidated the reciprocal regulation of 15-LOX enzymes and identified vitamin E-inspired dual inhibitors, which may improve pharmacological therapies of inflammation-associated diseases.