An intracrine view of sex steroids, immunity, and metabolic regulation - PubMed (original) (raw)

Review

An intracrine view of sex steroids, immunity, and metabolic regulation

Katya B Rubinow. Mol Metab. 2018 Sep.

Abstract

Background: Over the past two decades, parallel recognition has grown of the importance of both sex steroids and immune activity in metabolic regulation. More recently, these discrete areas have been integrated in studies examining the metabolic effects of sex steroid immunomodulation. Implicit in these studies has been a traditional, endocrine model of sex steroid delivery from the gonads to target cells, including immune cells. Thus, research to date has focused on the metabolic effects of sex steroid receptor signaling in immune cells. This endocrine model, however, overlooks the extensive capacity of immune cells to generate and metabolize sex steroids, enabling the production of sex steroids for intracrine signaling - that is, sex steroid production for signaling within the cell of origin. Intracrine function allows highly cell-autonomous regulation of sex steroid exposure, and sex steroid secretion by immune cells could confer paracrine signaling effects in neighboring cells within metabolic tissues. In this review, immune cell intracrinology will denote sex steroid production within immune cells for either intracrine or paracrine signaling. This intracrine capacity of immune cells has been well established, and prior work has supported its importance in autoimmune disorders, trauma, and cancer. The potential relevance of immune cell intracrine function to the regulation of energy balance, body weight, body composition, and insulin sensitivity has yet to be explored.

Scope of review: The following review will detail findings to date regarding the steroidogenic and steroid metabolizing capacity of immune cells, the regulation of immune cell intracrine function, and the biological effects of immune-derived sex steroids, including the clinical relevance of immune cell intracrinology in fields other than metabolism. These findings will serve as the basis for a proposed model of immune cell intracrinology constituting a new frontier in metabolism research.

Major conclusions: The development of highly sensitive mass spectrometric methods for sex steroid measurement and quantitation of metabolic flux now allows unprecedented ability to interrogate sex steroid production, metabolism and secretion by immune cells. Immune cell intracrinology could reveal key mechanisms underlying immune cell-mediated metabolic regulation.

Keywords: Androgens; Estrogens; Intracrine; Lymphocytes; Macrophages; Metabolism.

Copyright © 2018 The Author. Published by Elsevier GmbH.. All rights reserved.

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Figures

Figure 1

Figure 1

Immune cell intracrinology. In an endocrine model of sex steroid biology, sex steroids are synthesized in classically steroidogenic tissues and disseminated to target cells through the circulation. In contrast, immune cell intracrinology denotes the capacity of immune cells to synthesize, modify, and metabolize sex steroids. Sex steroids signal through nuclear receptors, and a membrane receptor (GPR30) also has been identified for estrogen signaling. Therefore, intracrine function in immune cells can generate sex steroids and their derivatives that mediate intracrine, autocrine, and paracrine effects.

Figure 2

Figure 2

Steroidogenic enzymes involved in the de novo synthesis of sex steroids from cholesterol. Green font indicates that enzyme activity has yet to be demonstrated in immune cells. Orange font indicates that enzyme activity has been demonstrated in macrophages, T lymphocytes, and B lymphocytes. Blue font indicates that enzyme activity has been demonstrated in macrophages and T lymphocytes only.

Figure 3

Figure 3

Schematic of the proposed mechanisms by which sex steroid generation in immune cells could confer metabolic effects. Sex steroids could remain within the cell of origin and act as ligands for cognate nuclear receptors (intracrine signaling). Alternatively, sex steroids could be secreted from the cell and signal through membrane receptors on the same cell (autocrine effects). As sex steroids have demonstrated roles in regulating immune cell differentiation, proliferation, and production of other paracrine mediators, these intracrine and autocrine effects could be key regulators of cellular phenotype and function. Further, secreted sex steroids also could exert signaling effects in neighboring cells (paracrine effects). Estrogens and androgens are important regulators of insulin sensitivity and energy metabolism in key metabolic tissues; thus, tissue resident immune cells could prove an important source of tissue-specific sex steroid production. Adipocytes and other cell types in adipose tissue also express steroidogenic enzymes including aromatase, suggesting that sex steroids could be key signals for cellular crosstalk within metabolic tissues.

Figure 4

Figure 4

Reciprocal regulation of steroidogenic enzymes and other signaling nodes. Cytokines, prostanoids, and growth factors regulate the expression and/or activity of steroidogenic enzymes, and sex steroids, in turn, have been shown to regulate the production of these autocrine and paracrine mediators. Similarly, many nuclear receptors act as both regulators of steroidogenic enzymes and targets of sex steroid signaling. Thus, sex steroid generation may be a central facet of immune cell phenotype and function.

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