Tuberculosis (TB) accounts for increased morbidity and mortality across the world. Approximately 10 million new TB cases emerge, and 1.5 million people die of this disease every year [1]. Host defense against mycobacteria which is critical for infection containment involves an inflammatory reaction in which innate and adaptive immune mechanisms play an active role in this regard [2]. Individuals are infected by the inhalation of airborne droplet nuclei containing Mycobacterium tuberculosis. In the lungs, M. tuberculosis mainly infects and resides in alveolar macrophages and dendritic cells, or monocytes recruited from peripheral blood. Macrophages generally constitute an effective initial barrier against infection by bacterial pathogens. Among immunocompetent hosts, the immune system would keep the infection in check using mechanisms that prevent further bacillary proliferation and limit the spreading of the organism [3], [4].

Within the wide range of responses aimed at containing M. tuberculosis, the lung possesses a group of fundamental mediators of innate immunity called host defense peptides (HDPs). Among these molecules, cathelicidin LL37, β-defensin-2 (HBD-2), and β-defensin-3 (HBD-3) play a crucial role in the immune response against mycobacteria [5], [6]. Specifically, it was observed that when M. tuberculosis infects cells from the lung epithelium, they produce high amounts of HBD-2, which binds to the mycobacterium, forming pores and eliminating it through osmotic shock [7]. Similar findings were seen in a mouse model of experimental TB, in parallel to the fact that mice susceptible to the disease produced fewer defensins compared to resistant animals. In the same way, it was observed that when resistant TB is rendered deficient in the expression of β-defensin-2, TB develops [8], [9]. While, LL-37 exerts a wide range of biological effects, including weak direct antimicrobial and chemotactic functions [10], [11], promotion of antimicrobial functions of neutrophils and macrophages [12], [13], and modulation of cell survival and apoptosis [14], [15].

In the context of the central role of macrophages in the defense against TB, we have recently demonstrated that dehydroepiandrosterone -DHEA- in the presence of cortisol reduced the intracellular mycobacterial load, inducing autophagy in cultured macrophages, and favoring better infection control [16]. Further studies from our laboratory also found a positive correlation between the plasma levels of cortisol and HBD-3 and DHEA and LL-37 among patients with severe TB, suggesting some relationship between the presence of HDPs and adrenal steroids [6].

Within this setting, nothing is known about whether HDPs may reciprocally influence adrenal steroidogenesis, a fundamental process in the survival of mammals. In humans, adrenal steroids are synthesized de novo in the adrenal cortex, which is histologically and functionally divided into three concentric zones: the outer glomerulosa zone (the only source of the mineralocorticoid aldosterone), the intermediate fascicular zone producing glucocorticoids (cortisol and corticosterone) and the internal reticular zone in which DHEA and its sulfated derivative (DHEAS) predominate being produced by a reaction catalyzed by the SULT2A1 enzyme [17], [18], [19]. Steroid hormones are synthesized from the cholesterol, which must be transported to the inner mitochondrial membrane, an assisted process requiring the synthesis of the acute Steroidogenesis Regulatory Protein (StaR) which constitutes a limiting step of the steroids production [20]. De novo synthesis of steroid hormones begins with the formation of pregnenolone from cholesterol. This reaction is catalyzed by the Cyp11A-encoded enzyme, cytochrome P450scc, found in the inner mitochondrial membrane. Subsequently, pregnenolone is converted into progesterone by the enzyme 3β-hydroxysteroid dehydrogenase type 2 (3β-HSD2) whereas the enzyme is encoded by Cyp17A1, and P450c17 further catalyzes the essential step for the formation of both glucocorticoids and androgens. This enzyme has two enzymatic activities, the first one (P45017A) is to catalyze the hydroxylation of pregnenolone and progesterone to generate 17α-hydroxypregnenolone and 17α-hydroxyprogesterone respectively, which by the action of P450c2, encoded by Cyp21A2, gives rise to 11-dexoxycortisol and finally to cortisol. The second activity (P45017B) catalyzes the cleavage of these products to form DHEA and androstenedione [17].

Beyond the classical mechanisms regulating adrenal steroid production, that is the hypothalamic–pituitaryadrenal (HPA) axis [21], there is also evidence of a local regulatory effect of products from the immune system on the adrenal gland [22].

From the foregoing, we sought to study the bidirectional relationship between the endocrine system and the innate immune response through the analysis of some of their components such as adrenal hormones and HDPs, in the context of M. tuberculosis infection. To this end, we first assessed the modulating effect of different doses of cortisol and/or DHEA on the production and biosynthesis of LL-37, HBD-2, and HBD-3 in THP1-derived macrophages infected or stimulated with M. tuberculosis. Conversely, we analyzed the effect of different concentrations of LL-37 on the production and release of cortisol and DHEA, as well as the expression of the transcripts of the enzymes involved in steroidogenesis in the human adrenal line NCI-H295-R.