Nuclear Receptors

Nuclear receptors are a class of transcription factors that act as master regulators of many different cellular and immunological processes, such as metabolism, cytokine production, and programmed cell death. Nuclear receptors are classified as conventional, orphan, or adopted orphan depending on whether an endogenous ligand has been identified. Upon binding a ligand, nuclear receptors can translocate from the cytoplasm to the nucleus to exert their transcription factor effects, although same nuclear receptors may already be present in the nucleus. It is known that different nuclear receptors may be permissive or restrictive to M.tb growth, even within the same family. Nuclear receptors are bona fide drug targets and an attractive target for host-directed therapies (HDTs). Our lab has studied the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) and shown that counteracting PPARγ’s effectors, such as MCL-1 and BCL2, induces apoptosis in macrophages and significantly decreases M.tb growth. Ongoing projects in the lab center on PPARγ and other nuclear receptors that are important for the host response to M.tb.

Selected Publications

  • Arnett, Eusondia, Susanta Pahari, Chrissy M Leopold Wager, Elizabeth Hernandez, Jordan R Bonifacio, Miranda Lumbreras, Charles Renshaw, Maria J Montoya, Joseph T Opferman, and Larry S Schlesinger. (2023) 2023. “Combination of MCL-1 and BCL-2 Inhibitors Is a Promising Approach for a Host-Directed Therapy for Tuberculosis.”. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 168: 115738. https://doi.org/10.1016/j.biopha.2023.115738.

    Tuberculosis (TB) accounts for 1.6 million deaths annually and over 25% of deaths due to antimicrobial resistance. Mycobacterium tuberculosis (M.tb) drives MCL-1 expression (family member of anti-apoptotic BCL-2 proteins) to limit apoptosis and grow intracellularly in human macrophages. The feasibility of re-purposing specific MCL-1 and BCL-2 inhibitors to limit M.tb growth, using inhibitors that are in clinical trials and FDA-approved for cancer treatment has not be tested previously. We show that specifically inhibiting MCL-1 and BCL-2 induces apoptosis of M.tb-infected macrophages, and markedly reduces M.tb growth in human and murine macrophages, and in a pre-clinical model of human granulomas. MCL-1 and BCL-2 inhibitors limit growth of drug resistant and susceptible M.tb in macrophages and act in additive fashion with the antibiotics isoniazid and rifampicin. This exciting work uncovers targeting the intrinsic apoptosis pathway as a promising approach for TB host-directed therapy. Since safety and activity studies are underway in cancer clinics for MCL-1 and BCL-2 inhibitors, we expect that re-purposing them for TB treatment should translate more readily and rapidly to the clinic. Thus, the work supports further development of this host-directed therapy approach to augment current TB treatment.

  • Arnett, Eusondia, Ashlee M Weaver, Kiersten C Woodyard, Maria J Montoya, Michael Li, Ky Hoang V, Andrew Hayhurst, Abul K Azad, and Larry S Schlesinger. (2018) 2018. “PPARγ Is Critical for Mycobacterium Tuberculosis Induction of Mcl-1 and Limitation of Human Macrophage Apoptosis.”. PLoS Pathogens 14 (6): e1007100. https://doi.org/10.1371/journal.ppat.1007100.

    Peroxisome proliferator-activated receptor (PPAR)γ is a global transcriptional regulator associated with anti-inflammatory actions. It is highly expressed in alveolar macrophages (AMs), which are unable to clear the intracellular pathogen Mycobacterium tuberculosis (M.tb). Although M.tb infection induces PPARγ in human macrophages, which contributes to M.tb growth, the mechanisms underlying this are largely unknown. We undertook NanoString gene expression analysis to identify novel PPARγ effectors that condition macrophages to be more susceptible to M.tb infection. This revealed several genes that are differentially regulated in response to PPARγ silencing during M.tb infection, including the Bcl-2 family members Bax (pro-apoptotic) and Mcl-1 (pro-survival). Apoptosis is an important defense mechanism that prevents the growth of intracellular microbes, including M.tb, but is limited by virulent M.tb. This suggested that M.tb differentially regulates Mcl-1 and Bax expression through PPARγ to limit apoptosis. In support of this, gene and protein expression analysis revealed that Mcl-1 expression is driven by PPARγ during M.tb infection in human macrophages. Further, 15-lipoxygenase (15-LOX) is critical for PPARγ activity and Mcl-1 expression. We also determined that PPARγ and 15-LOX regulate macrophage apoptosis during M.tb infection, and that pre-clinical therapeutics that inhibit Mcl-1 activity significantly limit M.tb intracellular growth in both human macrophages and an in vitro TB granuloma model. In conclusion, identification of the novel PPARγ effector Mcl-1 has determined PPARγ and 15-LOX are critical regulators of apoptosis during M.tb infection and new potential targets for host-directed therapy for M.tb.

  • Wager, Chrissy M Leopold, Eusondia Arnett, and Larry S Schlesinger. (2019) 2019. “Mycobacterium Tuberculosis and Macrophage Nuclear Receptors: What We Do and Don’t Know.”. Tuberculosis (Edinburgh, Scotland) 116S: S98-S106. https://doi.org/10.1016/j.tube.2019.04.016.

    Nuclear receptors (NRs) are ligand-activated transcription factors that are expressed in a wide variety of cells and play a major role in lipid signaling. NRs are key regulators of immune and metabolic functions in macrophages and are linked to macrophage responses to microbial pathogens. Pathogens are also known to induce the expression of specific NRs to promote their own survival. In this review, we focus on the NRs recently shown to influence macrophage responses to Mycobacterium tuberculosis (M.tb), a significant cause of morbidity and mortality worldwide. We provide an overview of NR-controlled transcriptional activity and regulation of macrophage activation. We also discuss in detail the contribution of specific NRs to macrophage responses to M.tb, including influence on macrophage phenotype, cell signaling, and cellular metabolism. We pay particular attention to PPARγ since it is required for differentiation of alveolar macrophages, an important niche for M.tb, and its role during M.tb infection is becoming increasingly appreciated. Research into NRs and M.tb is still in its early stages, therefore continuing to advance our understanding of the complex interactions between M.tb and macrophage NRs may reveal the potential of NRs as pharmacological targets for the treatment of tuberculosis.

  • Wager, Chrissy M Leopold, Eusondia Arnett, and Larry S Schlesinger. (2019) 2019. “Macrophage Nuclear Receptors: Emerging Key Players in Infectious Diseases.”. PLoS Pathogens 15 (3): e1007585. https://doi.org/10.1371/journal.ppat.1007585.

    Nuclear receptors (NRs) are ligand-activated transcription factors that are expressed in a variety of cells, including macrophages. For decades, NRs have been therapeutic targets because their activity can be pharmacologically modulated by specific ligands and small molecule inhibitors. NRs regulate a variety of processes, including those intersecting metabolic and immune functions, and have been studied in regard to various autoimmune diseases. However, the complex roles of NRs in host response to infection are only recently being investigated. The NRs peroxisome proliferator-activated receptor γ (PPARγ) and liver X receptors (LXRs) have been most studied in the context of infectious diseases; however, recent work has also linked xenobiotic pregnane X receptors (PXRs), vitamin D receptor (VDR), REV-ERBα, the nuclear receptor 4A (NR4A) family, farnesoid X receptors (FXRs), and estrogen-related receptors (ERRs) to macrophage responses to pathogens. Pharmacological inhibition or antagonism of certain NRs can greatly influence overall disease outcome, and NRs that are protective against some diseases can lead to susceptibility to others. Targeting NRs as a novel host-directed treatment approach to infectious diseases appears to be a viable option, considering that these transcription factors play a pivotal role in macrophage lipid metabolism, cholesterol efflux, inflammatory responses, apoptosis, and production of antimicrobial byproducts. In the current review, we discuss recent findings concerning the role of NRs in infectious diseases with an emphasis on PPARγ and LXR, the two most studied. We also highlight newer work on the activity of emerging NRs during infection.