Extra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders

Abstract

Glucocorticoid synthesis is a complex, multistep process that starts with cholesterol being delivered to the inner membrane of mitochondria by StAR and StAR-related proteins. Here its side chain is cleaved by CYP11A1 producing pregnenolone. Pregnenolone is converted to cortisol by the enzymes 3-βHSD, CYP17A1, CYP21A2, and CYP11B1. Glucocorticoids play a critical role in the regulation of the immune system and exert their action through the glucocorticoid receptor (GR). Although corticosteroids are primarily produced in the adrenal gland, they can also be produced in a number of extra-adrenal tissue including the immune system, skin, brain, and intestine. Glucocorticoid production is regulated by ACTH, CRH, and cytokines such as IL-1, IL-6, and TNFα. The bioavailability of cortisol is also dependent on its interconversion to cortisone, which is inactive, by 11βHSD1/2. Local and systemic glucocorticoid biosynthesis can be stimulated by ultraviolet B, explaining its immunosuppressive activity. In this review, we want to emphasize that dysregulation of extra-adrenal glucocorticoid production can play a key role in a variety of autoimmune diseases including multiple sclerosis (MS), lupus erythematosus (LE), rheumatoid arthritis (RA), and skin inflammatory disorders such as psoriasis and atopic dermatitis (AD). Further research on local glucocorticoid production and its bioavailability may open doors into new therapies for autoimmune diseases.

Figure 1.

The biochemical pathway of steroidogenesis. Glucocorticoid synthesis is in bold. DHCR7: 7-delta reductase; 3βHSD: 3β-hydroxysteroid dehydrogenase

Figure 2.

The functional organization of the hypothalamic-pituitary-adrenal axis with inputs from the immune system and the skin. Physical and biological stress promotes the release of stress signals in both the brain, the skin, and immune cells, resulting in the hypothalamic release of CRH, which in turn stimulates the release of ACTH and POMC expression and processing in the anterior pituitary. ACTH binds to the MC-2 receptor in the zona fasciculata of the adrenal cortex and stimulates the transport of cholesterol into the mitochondria and stimulates the production cortisol. Glucocorticoids not only regulate body homeostasis but also act in a negative feedback loop for CRH and POMC expression. Re-use of some elements of schematic figure from Dr Slominski Commentary is with permission from the Journal of Clinical Investigation.

Figure 3:

CYP11A1 expression in human peripheral blood mononuclear cells (PBMCs).The left dot plot shows CD4, CD8 T cells, and CD4⁻CD8⁻ cells in PBMCs. The right histogram shows expression of CYP11A1 in gated CD4 cells, CD8 T cells, and CD4⁻CD8⁻ cell populations verses the unstained PBMC. The blood was obtained from a healthy volunteer (IRB 160426001) and processed as described previously. Intracellular staining for CYP11A1 (Cell signaling technology; Danvers, MA, USA) was performed in cells fixed with paraformaldehyde and permeabilized in methanol containing buffer ^, . Anti- Cyp11A1 was conjugated to APC-Cy7 (Abcam; Cambridge, UK) as per manufacturers protocol before use. Stained cells were analyzed using a BD-FACS Symphony flow cytometer (BD Biosciences, San Jose, CA). Data are representative of three independent experiments utilizing different donors.

Figure 4:

Expression of StAR and CYP11A1 in HaCaT cells (human epidermal keratinocytes). The intracellular expression of StAR and CYP11A1 in HaCaT cells was determined using Image Stream II (Amnis, Seattle, WA, USA) cytometer as described previously . Dot plots from left to right depict Area vs Aspect ratio (strategy to gate on single cells); StAR vs mitochondria; CYP11A1 vs mitochondria; and StAR vs CYP11A1. The 1:1 (diagonal) expression of StAR with mitochondria indicated their tightly linked expression and potential co-localization. Positive correlation between expression of CYP11A1 and mitochondria and between StAR and CYP11A1 indicate linked expression with each other and perhaps co-localization in the mitochondria. The HaCaT keratinocytes were detached and processed as previously described. The cells were fixed and stained with antibodies to Cyp11A1 (Cell signaling technology; Danvers, MA, USA) StAR (Santa Cruz; Dallas, TX, USA), and Mitotracker Red (CMX Ros Invitrogen; Carlsbad, CA, USA) at 10 nM as described previously. Data were analyzed using IDEAS software (Amnis, Seattle, WA, USA).

Figure 5.

Local cortisol/corticosterone levels can control immune functions and inflammatory responses in a Yin/Yang manner.