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.