Androgens inhibit phagocytosis by macrophages via the androgen receptor in vitro

Parry, Chloe (2018) Androgens inhibit phagocytosis by macrophages via the androgen receptor in vitro. Masters by Research thesis (MSc), Manchester Metropolitan University.

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Abstract

The cost to healthcare services for the treatment of chronic wounds exceeds $3 billion per year (Menke et al, 2007). Chronic wounds are frequently colonised by nosocomial opportunistic pathogens such as Methicillin-resistant Staphylococcus aureus (MRSA). Endogenous androgens are known to contribute to delayed healing whilst in contrast, estrogen accelerates healing. Healing in the elderly is impaired, particularly in elderly males due to the concomitant decline in estrogen levels yet largely unchanged levels of circulating androgens. This is predominantly characterised by a prolonged inflammatory phase during wound repair. In this study a host-pathogen interaction assay was used to investigate the effect of the two main endogenous androgens, testosterone (T) and dihydrotestosterone (DHT), on the clearance of MRSA by macrophages derived from U937 monocytes. Concentrations of T and DHT were chosen to model adult supraphysiological levels following exogenous supplementation (1 x 10-6 M), physiological levels (1 x 10-7 M, 1 x 10-8 M) and androgen deprivation (1 x 10-9 M). The involvement of androgen receptor (AR) activation in bacterial clearance was explored using AR pathway inhibitors. Supraphysiological and physiological levels of androgens typical of that in adulthood significantly (P<0.05; n=24) inhibited phagocytosis of MRSA in a concentration-dependent manner compared to the untreated negative control. Scanning electron microscopy (SEM) confirmed androgens inhibit bacterial internalisation by U937 macrophages. AR antagonism reversed the effects of T and DHT, significantly (P<0.05) enhancing phagocytosis to levels observed in the untreated negative control. These findings suggest androgens inhibit the resolution of typical wound bacteria by impairing macrophage-mediated phagocytosis, a phenomenon that can be reversed via direct AR antagonism. More importantly, the 5alpha-reductase inhibitor finasteride significantly (P<0.05; n=24) increased the clearance of MRSA, suggesting the inhibition of phagocytosis by T is mediated principally through initial conversion of T to DHT, followed by AR activation by DHT. Novel wound dressings that provide local blockade of the AR or inhibition of 5alpha-reductase may be potential therapeutic treatments to promote the bacterial clearance of colonised wounds in elderly males.