Introduction
Type 2 Diabetes (T2D) is currently the most widespread susceptibility factor for tuberculosis (TB) with a high incidence and prevalence in low- and middle-income countries (1). In most cases, Mycobacterium tuberculosis (Mtb) infection is controlled by immune mechanisms that contribute to granuloma development and control of bacterial growth (2). However, recent research on TB-T2D comorbidity shows that innate and adaptive immunity are more affected when both conditions occur together than when only one disorder is present. (3).
A type 1 T helper (Th1) cell response mediates the protective immune response to TB through macrophages activation by IFN-γ and TNFα (4). Observations in T2D patients show an impaired response to Mtb infection (5), consisting in alterations in bacterial recognition, phagocytosis, and a deficient immune cellular response with low cytokine and chemokine production (6), resulting in severe TB manifestations (7).
A new aspect in understanding the higher susceptibility of T2D to develop TB is the study of the abnormal metabolic factors and neuro-immune-endocrine regulation in this co-morbidity. In homeostatic conditions and under acute or chronic stress, the principal source of glucocorticoids (GCs) are the adrenal glands regulated by the activation of the Hypothalamus-Pituitary-Adrenal (HPA) axis (8). Besides this source of circulating GCs, there is a local organ conversion of inactive to active GCs (9), which is mediated by the enzyme 11-β-hydroxysteroid dehydrogenase type 1 (11-βHSD1) that has an oxo-reductase activity using NADP(H) as a cofactor. This enzyme converts inactive cortisone to active cortisol in humans or corticosterone in rodents (10). Interestingly, there is another enzyme with the opposite effect. 11-β-hydroxysteroid dehydrogenase type 2 (11-βHSD2) acts exclusively as an NAD-dependent dehydrogenase that converts active cortisol or active corticosterone to inactive cortisone (11).
Although blood levels of glucocorticoids are in the normal range in T2D and TB, it seems that this is not the case in the lung and liver. Higher activity of 11-βHSD1 in these peripheral organs results in increased GC production in these organs.
GCs are critical homeostatic hormones that are overproduced after diverse environmental insults, and in general they have a negative effect on metabolism and the immune response (12). GCs exert their effects by binding to glucocorticoid receptors (GR) present in all cell types. Hence, GR signaling plays an essential role in the modulation of many biological functions in immune cells and several tissues, including liver, lung, adipose tissue, thymus and muscle (13).
Cortisol suppresses the expression of pro-inflammatory and adhesion molecules, thus preventing the extravasation of neutrophils to the site of inflammation (13). Chronic exposure induces an anti-inflammatory gene expression profile of resident macrophages and decreases their phagocytic activity. Furthermore, active GCs suppress Th1 cytokine production and induce cell death (14), promoting a Th2 environment that impairs granuloma formation (7). GCs inhibit the proliferation of effector T cells and induce apoptosis of neutrophils, basophils, and eosinophils resulting in reduced inflammation (15). GCs also have an important contribution in the physiopathology of TB. It has been reported in an experimental model of progressive TB that at the time of maximal protective activity mediated by IFN-γ, TNF-α and NO production, the hypothalamic-pituitary-adrenal axis is activated, thereby stimulating the adrenal glands to secrete GCs (corticosterone) with the apparent aim of avoiding tissue damage produced by excessive lung inflammation. However, the excess of corticosterone also inhibits Th1 lymphocytes activity and induces differentiation of Th-2 lymphocytes. This favors bacterial survival and proliferation, causing animals death (14). As far as we know, there are no published studies about the pulmonary production of active GCs mediated by 11-βHSD1 in TB.
In metabolic diseases such as obesity and metabolic syndrome, GCs play a role in the development of diabetes, but interestingly, GCs in the circulation have the same concentrations as healthy subjects (16). Experimental studies with transgenic mice overexpressing 11-βHSD1 selectively in adipose tissue demonstrate increased local levels of corticosterone that induce visceral obesity development, insulin resistance, diabetes, and hyperlipidemia (16). The increased conversion of active glucocorticoids in visceral adipose tissue increases lipolysis and fatty acid levels (17).
Moreover, active GCs are potent inducers of glycogenolysis and gluconeogenesis, resulting in a hyperglycemic state, deteriorating the condition of diabetic patients (18). 11-βHSD1 also increases glucose output by activating phosphoenolpyruvate kinase (PEPCK) gene expression in the liver (19). Thus, active GCs have direct implications in the abnormal metabolic control and chronic complications of T2D (20).
Regulation of cortisol is mediated by dehydroepiandrosterone (DHEA), an anabolic hormone of the adrenal cortex involved in the conversion of sexual steroids. This hormone displays antagonistic activity to cortisol, impacting the immune response (21) and glucose metabolism. The cortisol-DHEA ratio is modified in T2D-TB comorbidity and represents a deleterious factor for both diseases (8). 16α-Bromoepiandrosterone (BEA) is a synthetic analog hormone of DHEA that modulates immune and metabolic responses (22, 23). Compared to DHEA, BEA does not display anabolic activities.
Here, we studied the expression of 11-βHSD1 and 11-βHS2, as well as the concentrations of GCs during experimental late TB and T2D/TB in the lung and liver and evaluate the therapeutic effect of BEA administration in a murine model of T2D-TB comorbidity.