The role of macrophage steroid metabolism in chronic inflammation

Martin, Claire Syme (2023). The role of macrophage steroid metabolism in chronic inflammation. University of Birmingham. Ph.D.

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Abstract

Macrophages are central to both the pathology and resolution of chronic inflammatory diseases such as rheumatoid arthritis (RA). Steroid hormones such as glucocorticoids (GCs) and androgens are reported to be important modulators of macrophage functions. However, the role of intracrine and paracrine steroid metabolism in the regulation of macrophage inflammatory function in RA remains poorly understood. Using transcriptional analysis of human RA synovial macrophages, we showed that differential expression of steroidogenic enzymes: the GC-activating enzyme 11β-HSD1 and late androgen activating enzyme SRD5A1, expressed within pathogenic macrophage subsets, increased with inflammation, while the early androgen activator AKR1C3, expressed by protective macrophages, decreased with inflammation. In vitro monocyte-derived macrophages were used to interrogate steroidogenesis and effects of intracrine steroid metabolism on inflammatory functions relevant to RA. Intracrine GC metabolism increased with inflammatory polarisation, enabling acquisition of a pro-resolution phenotype at the expense of inflammatory functions on GC stimulation. Therapeutic targeting of this pathway to promote anti-inflammatory actions of GCs was assessed using sheared gellan hydrogels, with proof of principle studies showing selective inflammatory macrophage GC-mediated regulation. Androgen metabolism was strongly increased by pro-inflammatory polarisation of macrophages. Although intracrine androgen metabolism did not regulate inflammation, our data suggest a role for inflammatory macrophages as paracrine androgen activators. This thesis describes distinct patterns of inflammation-induced steroid metabolism in RA synovial macrophage subsets that could be exploited by novel therapeutics for inflammatory diseases.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):