Tuberculosis (TB) is one of the top ten causes of death worldwide. Until the coronavirus (COVID-19) pandemic, TB was the leading cause of death attributed to a single infectious agent, ranking above HIV/AIDS (Global Tuberculosis Report, 2022). According to WHO estimates, there were 10.6 million TB cases in 2021, reaching 1.4 million deaths, although these numbers are considered underestimates as the COVID-19 pandemic delayed global TB control services, reversing years of progress made in the fight against this disease (No Author, 2019).

TB is an ancient chronic infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb), which is spread when sick people expel bacteria into the air, for example, by coughing. The disease usually affects the lungs (pulmonary TB) but can also affect other body sites (extrapulmonary TB). Commonly, the host immune response (IR) controls Mtb replication, by promoting mycobacterial clearance or leading to the establishment of a latent infection, which ultimately depends on a fine balance between the pathogen and the specific IR (Ernst, 2012).

Mtb mainly infects macrophages (Mf) which need to be activated by the cellular IR for containing mycobacteria (Th1 pattern activation) (Russell, 2001; Hestvik et al., 2005; Jordao et al., 2008). Cytokines such as IFN-γ, secreted by T lymphocytes, and TNF-α are essential to achieve classical macrophage activation (M1) and intracellular pathogen elimination (Kaufmann, 2001; O’Garra et al., 2013). At the same time, an exacerbated IR and the ensuing excessive secretion of inflammatory mediators turn out to be detrimental to host tissues through immunopathological processes, which is quite pathognomonic of diseases of chronic nature like TB. In line with this, newly diagnosed TB patients (T0) show a marked consumption state together with a lower body mass index (BMI), in addition to an immune-endocrine-metabolic (IEM) imbalance (Santucci et al., 2011; Bottasso et al., 2013; Díaz et al., 2017). This mainly consists of increased circulating amounts of pro- and anti-inflammatory cytokines together with increased cortisol and lowered dehydroepiandrosterone (DHEA) values, partly associated with the degree of pulmonary involvement (Bottasso et al., 2013; Díaz et al., 2017; D’Attilio et al., 2018).

Within the broad array of regulatory processes which are likely to take place during Mtb infection, the contribution of the peroxisome proliferator-activated receptors (PPARs), which belong to the nuclear receptor superfamily, is worth exploring. PPARs are a family of 3 ligand-activated transcription factors: PPARα (NR1C1), PPARβ/δ NR1C2), and PPARγ (NR1C3). These PPARs are encoded by different genes but show similar structural features, which include an amino-terminal modulatory domain, a DNA binding domain, and a carboxyl-terminal ligand binding domain. All PPARs act as heterodimers with the retinoid X receptor (RXRs) and play important roles in the regulation of metabolic pathways, including those of lipid biosynthesis and glucose metabolism, as well as in a variety of cell functions: differentiation, proliferation, apoptosis pathways and inflammation (Blitek and Szymanska, 2017; Portius et al., 2017; Christofides et al., 2021).

PPAR ligands, in particular those of PPARα and PPARγ, inhibit the activation of inflammatory gene expression and can negatively interfere with proinflammatory transcription factor signaling pathways in vascular and inflammatory cells. Furthermore, PPAR levels are differentially regulated in a variety of inflammatory disorders in men, for which PPAR ligands may constitute promising therapies (Moraes et al., 2006). Evidence indicates that chronic metabolic diseases accompanied by immunological-endocrine disturbances, i.e., diabetes and metabolic syndrome, present a higher risk of infections together with a lower bactericidal capacity from the innate immune cells. In this regard, treatment with thiazolidinedione drugs like pioglitazone (synthetic PPARγ ligand), not only diminished the inflammation but also increased the capability of host cells to cope with pathogens, in addition to modulating hormone production and glucolipid homeostasis (Sharma et al., 2017). A study in a murine model of sepsis showed that treatment with the agonist pioglitazone improved mouse survival by enhancing the neutrophil bacterial clearance and promotion of an anti-inflammatory milieu at the site of infection (Ferreira et al., 2014). In the case of TB, some studies showed that mycobacterial infections coexist with an increased expression and activation of PPARγ at the Mf level which leads to changes in intracellular lipid homeostasis (foamy Mf) and its activation profile, promoting an M2 pattern more favorable to Mtb survival (Almeida et al., 2012).

Given this background and considering the substantial role of IEM disturbances in TB pathophysiology, we sought to investigate the relationship of PPARγ with some IEM components in the setting of clinical pulmonary TB, at the time of diagnosis and throughout the course of specific treatment to get a better understanding on their implication in the processes dealing with disease development and resolution. We also carried out in vitro experiments in a macrophage cell line for a more in deep analysis of the reciprocal influences between PPARγ and glucocorticoids.

The control of an infectious process depends on the type and magnitude of the defensive response that appears beneficial during the initial phase but may become harmful if prolonged due to pathogen persistence, as is the case of TB. Because of its chronic nature, TB coexists with an immuno-endocrine-metabolic imbalance and excessive inflammatory reactions accounting for the host impairment seen during the progressive disease (Bottasso et al., 2013). In fact, at the time of diagnosis, TB patients showed a decrease in their BMI, an excessive pro-inflammatory response (Díaz et al., 2017), together with an increased NLR. The latter may be a surrogate reflecting the balance between two facets of the defensive reaction: acute and chronic inflammation (Song et al., 2021) coexisting at the same time. Another feature of the inflammatory response during TB was the increased percentage of eosinophils, at T0 and during the specific treatment, which may be related to the recruitment of these cells to exert a protective role against infection (Prakash Babu et al., 2019; Bohrer et al., 2021).

The control of the proinflammatory response requires not only intrinsic regulatory mechanisms from both innate and adaptive immune systems but also the ones extrinsic to the immune system, for instance, the activation of the hypothalamic-pituitary-adrenal axis leading to cortisol production (Kaufmann, 2001) as well as other regulators of inflammatory or immune responses like PPARs.

Within this setting, we here provide novel evidence that PBMC from newly diagnosed patients with pulmonary TB has an increased expression of PPARγ transcript, related to the degree of lung involvement, proinflammatory plasma mediators, and cortisol levels. The increased PPARγ expression coupled with elevated plasma cortisol concentrations may mirror a regulatory attempt for the substantial inflammatory response that patients show at the time of diagnosis, aimed to ameliorate the tissue damage and return to homeostasis. Without being mutually exclusive, the concomitant rise of plasma cortisol levels and PPARγ transcripts in relation to disease severity may also reflect the degree of immuno-endocrine-metabolic imbalance. Extending our former results that plasma levels of proinflammatory mediators started to decrease by the second month of specific treatment (Díaz et al., 2017), we now show that PPARγ transcripts also decay by the same time point. Cortisol levels remained elevated throughout treatment (Díaz et al., 2017), suggesting a higher role of cortisol immunomodulation during disease recovery (Díaz et al., 2017).

While the changes in the peripheral compartment may not be an accurate reflection of the response that takes place at the injury site (D’Attilio et al., 2013), they bear some relationship with the extent of lung compromise, as specific anti-TB treatment induced a significant drop of PPARγ transcript expression and in proinflammatory mediators, possibly related to the lower bacterial burden (Sabiiti et al., 2020; Osei-Wusu et al., 2021).

There is evidence that PPARγ expression following TCR stimulation of T cells negatively regulates their activation by inhibiting the nuclear factor of activated T-cells (NFAT) and subsequent IL-2 production (Clark et al., 2000; Choi and Bothwell, 2012). Yang and col. also showed that the activation of this receptor in human T cells reduced IL-2 production and proliferation (Yang et al., 2000). This may help to explain our findings about the negative correlation between PPARγ and LTCD4+ cells seen in TB patients at the time of diagnosis, wherein the former was found to be significantly increased and the latter decreased. Further studies are needed to elucidate the appropriate meaning of this association. Whether PPARγ activation is also likely to promote the biased Th2 response seen in progressive TB (Stark et al., 2021) also remains to be established.

PPARs can be expressed in a variety of tissues and cell types including Mf (Chinetti et al., 1998; Rigamonti et al., 2008). These cells are among the first ones to encounter Mtb and play an important role in regulating the immune response against this pathogen. In Mf, PPARγ would act by modifying the expression of different inflammatory genes, modulating cell differentiation and activation through the trans-repression of different transcription factors such as NF-κB, AP-1, and STATs (Ricote et al., 1999), as well as diminishing the respiratory burst (von Knethen and Brune, 2002).

The expression of PPARs can also be increased upon pathogen exposures (Penas et al., 2013). In this regard, up-regulation of PPARγ expression on Mf after infection by Mycobacterium bovis (BCG), Mtb, Listeria monocytogenes, and Mycobacterium leprae has been reported (Straub et al., 2002; Chan et al., 2010; Rajaram and Brooks, 2010; Mahajan et al., 2012). Almeida et al. demonstrated that infection with Mtb increases the expression and activation of PPARγ leading to an enhanced formation of lipid droplets (foamy Mf), in addition to modifying the activation profile of Mf (inhibition of proinflammatory cytokines) inducing an M2 profile (Almeida et al., 2012). Furthermore, Guerrini et al. showed that during Mtb infection, the development of Mf into foam cells involves the activation of signaling pathways leading to intracellular triglycerides accumulation, driven by TNF receptor signaling and the downstream activation of the caspase cascade and the mammalian target of rapamycin complex 1 (mTORC1) (Guerrini et al., 2018). Both mechanisms favor mycobacterial survival.

Regarding PPARγ, recognition of Mtb by Mf mannose receptor activates mitogen-activated protein kinase (MAPK)-p38-cytosolic phospholipase A2 (cPLA2), resulting in hydrolysis and release of arachidonic acid from the plasma membrane to generate prostaglandin E2 (PGE2) and cyclopentenone prostaglandins (15-d-PGJ2) (Rajaram and Brooks, 2010). These two compounds are natural ligands of PPARγ, for which they are likely to activate the receptor pathways in these cells. In line with this, present results showed that Mtb stimulation of THP1-Mf significantly increased pro and anti-inflammatory cytokines (IL-1β and IL-10) as well as PPARγ expression, whereas the activation of this receptor by a specific natural agonist diminished the expression of these cytokines in stimulated Mf at the early step of immune response (Ricote et al., 1999). Stimulated cultures treated with cortisol together with the PPARγ agonist showed the lowest levels of the proinflammatory cytokine IL-1β, suggestive of intercommunication between both immunomodulatory mechanisms. However, treatment with RU486 only reversed the inhibitory effect of GC without modifying the one exerted by PPARγ activation. This suggests that both effects may be mediated through different intracellular pathways, as reported by Yamamoto et al. in a mouse model of acute inflammation (Yamamoto et al., 2014). Although in studies employing colonic epithelial cells, cortisol was likely to control the expression of PPARγ (Bouguen et al., 2014).

In non-infectious chronic diseases, i.e., metabolic syndrome or diabetes, the use of PPARγ agonists, like TZDs (including rosiglitazone and pioglitazone), showed some effectiveness in parallel to side effects such as increased weight gain, fluid retention, bone loss, congestive heart failure, etc. (50), which led to its discontinuation as was the case of rosiglitazone (51). This stimulated the search for new antagonists exempted from such adverse effects. Our results along with the relevance of lipid metabolism in the pathogenesis of TB and Mtb survival, as well as the fact that PPARγ deletion in pulmonary Mfs improved the course of murine tuberculosis (52), provide no evidence to think about the potential use of a PPARγ agonist in TB.

In getting a better understanding of the role of PPARγ in the host-mycobacteria relationship, our study provides the first evaluation of the expression of PPARγ in PBMC from TB patients according to the extent of lung damage and specific treatment. Results provide a stimulating background for further analysis of the interrelation between PPARs and the immune-endocrine framework of this particular disease.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the study protocol by the Ethical Committee of the Faculty of Medical Science, National University of Rosario (Resolution n° 44405/0005) and the Centenario Hospital of Rosario (Resolution n° 528). The patients/participants provided their written informed consent to participate in this study.

All authors have contributed to this project. All authors have read and agreed to the published version of the manuscript.