A novel microRNA signalling pathway in macrophages linking glucocorticoids and cellular metabolism

Clayton, Sally Anne (2020). A novel microRNA signalling pathway in macrophages linking glucocorticoids and cellular metabolism. University of Birmingham. Ph.D.

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Abstract

Glucocorticoids are frequently used to treat chronic inflammatory diseases due to their potent anti-inflammatory properties, but long-term use can cause severe side effects. We therefore require a better understanding of the mechanisms by which glucocorticoids achieve their desirable anti-inflammatory actions. This study aimed to investigate the role of a class of regulatory RNAs – microRNAs – in glucocorticoid function in macrophages, as this cell type represents a major target of glucocorticoids.

The microRNA miR-147b was upregulated by lipopolysaccharide and inhibited by glucocorticoid in macrophages, and was predicted to target metabolic pathways. The mitochondrial electron transport chain protein NDUFA4 was shown to be a functional target of miR-147b. NDUFA4 was strongly downregulated by toll-like receptor stimulation, and expression was partially rescued by glucocorticoid. Silencing of NDUFA4 enhanced the glycolytic shift that occurs upon macrophage inflammatory stimulation.

Glucocorticoids were shown to regulate macrophage metabolic processes, most notably the strong inhibition of glycolysis during lipopolysaccharide treatment. Clear differences in metabolic response were also demonstrated between mouse and human macrophages, which has translational implications for the field of immunometabolism.

This work identified a pathway linking glucocorticoid action to the regulation of macrophage metabolism through the action of miR-147b, which could impact cellular function and glucocorticoid efficacy.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):