Abstract
The battle against tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (M.tb), remains critical, demanding novel therapeutic interventions. Nuclear receptors (NRs), which are ligand-activated transcription factors, have recently been identified as significant players in the modulation of host immune defenses during M.tb infection. This article delves into the intricate relationship between NRs, especially PPARγ, and their role in macrophage responses to TB, paving the way for NRs as potential pharmacological targets. The insights discussed herein are underpinned by the review published in Tuberculosis (Edinburgh, Scotland) titled “Mycobacterium tuberculosis and macrophage nuclear receptors: What we do and don’t know.”
Introduction
TB remains one of the leading causes of death from infectious diseases globally (Global tuberculosis report 2017. Geneva: World Health Organization, 2017 CC BY-NC-SA 3.0 IGO). Despite advancements in medicine, the complex interplay between M.tb and the human immune system continues to challenge researchers and healthcare providers alike. Recently, a new frontier has been identified in the form of NRs, which are intracellular proteins crucial for regulating genes responsible for maintaining cellular homeostasis, metabolism, and immune responses (Chawla A et al., 2001).
A groundbreaking review by Leopold Wager CM and colleagues builds upon this knowledge by exploring how M.tb infection modulates NR activity, particularly that of PPARγ, in macrophages (DOI: 10.1016/j.tube.2019.04.016). This article aims to elaborate on the findings and implications of their research, which has been supported by grants R01 AI052458, R01 AI059636, R01 AI059639, R21 AI052458 from the National Institutes of Health (NIH).
The Role of Nuclear Receptors in Macrophage Responses to TB
NRs, such as PPARγ, LXR, and RXR, are known to interact with specific ligands to regulate gene expression that influences an array of cellular processes, including metabolism and immune responses (Aranda A and Pascual A, 2001). Macrophages, the primary host cells that M.tb infects, have been found to express various NRs that alter their response to the pathogen (Glass and Saijo, 2010). The review by Leopold Wager CM et al. focuses on the recent evidence that identifies a prominent role of PPARγ in the differentiation and function of alveolar macrophages, which are a critical niche for M.tb survival and proliferation (Han M et al., 2014).
PPARγ, in particular, takes center stage in this context. It is a NR known for its role in lipid metabolism and adipogenesis, but its role in immune response modulation is gaining increasing attention. Its activation during M.tb infection seems to have a dual role: aiding in the bacterium’s survival while simultaneously limiting macrophage activation (Mahajan S et al., 2012).
Addressing the Double-Edged Sword of PPARγ Activation in TB
While PPARγ offers M.tb a survival advantage by maintaining an anti-inflammatory environment, this NR also contributes to the regulation of immune responses that facilitate bacterial clearance. For instance, PPARγ aids in the production of antimicrobial peptides that are critical in the innate immune response against the bacterium (Rajaram MV et al., 2010). Moreover, it has been shown that PPARγ agonists can enhance macrophage function, upregulating the machinery responsible for bacterial digestion and antigen presentation (Arnett E et al., 2018).
The balance of PPARγ activation, therefore, represents a potential therapeutic target, with the aim of inhibiting its bacterial survival functions while promoting its immunoregulatory roles.
Exploring Potential NR-Based Therapeutics
The insights presented in the reviewed work advocate for the exploration of NR agonists and antagonists as adjunctive therapies in TB treatment. By modulating macrophage activation and function, these compounds could alter the course of the disease. A particular focus has been given to molecules that can selectively inhibit PPARγ’s pathological effects while bolstering its beneficial immune-regulatory roles (Chandra V et al., 2015).
Repurposing existing NR-modulating drugs, such as those used in the treatment of dyslipidemia and diabetes, offers a promising short-cut in the drug development process for TB therapies. Statins, for example, have been studied for their anti-inflammatory effects and could potentially play an adjuvant role in TB treatment regimens (Su VY et al., 2017).
Knowledge Gaps and Future Research Directions
While the review by Leopold Wager CM et al. presents exciting advances in the field, it is also candid about the existing knowledge gaps. The full spectrum of NRs involved in TB infection has yet to be delineated. Moreover, understanding the various ligands, both endogenous and synthetic, that influence these receptors’ actions during M.tb infection is an area ripe for further research.
Future studies need to dissect the temporal dynamics of NR expression and activity following M.tb infection to map their exact roll-out during the course of the disease. Additionally, clinical trials are needed to assess the efficacy and safety of NR-targeted therapies in TB patients.
Conclusion
The emergence of NRs as viable targets in the battle against TB represents a promising avenue for novel therapeutic interventions. The review by Leopold Wager CM et al. serves as a stepping stone for the scientific community, encouraging further investigation into the nuanced role of NRs such as PPARγ in TB pathogenesis and treatment.
References
1. Global tuberculosis report 2017. Geneva: World Health Organization, 2017 CC BY-NC-SA 3.0 IGO.
2. Mahajan S, et al. Mycobacterium tuberculosis modulates macrophage lipid-sensing nuclear receptors PPAR gamma and TR4 for survival. J Immunol, 2012. 188(11): p. 5593–603. DOI: 10.4049/jimmunol.1103096
3. Rajaram MV, et al. Mycobacterium tuberculosis activates human macrophage peroxisome proliferator-activated receptor gamma linking mannose receptor recognition to regulation of immune responses. J Immunol, 2010. 185(2): p. 929–42. DOI: 10.4049/jimmunol.0903089
4. Arnett E, et al. PPARγ is critical for Mycobacterium tuberculosis induction of Mcl-1 and limitation of human macrophage apoptosis. PLoS Pathog, 2018. 14(6): e1007100. DOI: 10.1371/journal.ppat.1007100
5. Chandra V, et al. NR1D1 ameliorates Mycobacterium tuberculosis clearance through regulation of autophagy. Autophagy, 2015. 11(11): p. 1987–1997. DOI: 10.1080/15548627.2015.1091142
6. Leopold Wager CM, Arnett E, Schlesinger LS. Mycobacterium tuberculosis and macrophage nuclear receptors: What we do and don’t know. Tuberculosis (Edinburgh, Scotland), 2020. 116S: S98-S106. DOI: 10.1016/j.tube.2019.04.016
Keywords
1. Tuberculosis treatment
2. Nuclear receptors TB
3. PPARγ tuberculosis
4. Macrophage TB therapy
5. NR agonists tuberculosis