Macrophage nuclear receptors: Emerging key players in infectious diseases

Abstract

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.

Fig 1. PPARγ structure and signaling in macrophages.

NRs have a highly conserved structure with an N-terminal transactivation domain and a DNA-binding domain and C-terminal ligand-binding domain that are connected by a hinge region. Upon activation, the NR PPARγ heterodimerizes with RXR, binds to PPREs, and initiates transcription of target genes initiating various signaling pathways in macrophages. PPARγ signaling is induced in macrophages following infection with several pathogens, including bacteria, parasites, and viruses. During infection, PPARγ signaling has been linked to increased wound-healing responses, M2 macrophages, phagocytosis, and decreased inflammation. PPARγ has also been linked to decreased apoptosis and increased lipid uptake in macrophages. Conversely, PPARγ has been linked to both reduced and increased ROS production, including increased mitochondrial ROS production in the absence of NADPH oxidase. Arg1, arginase 1; CD36, cluster of differentiaion 36; MR, mannose receptor; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κb, nuclear factor kappa B; NR, nuclear receptor; PPARγ, peroxisome proliferator-activated receptor gamma; PPRE, PPAR response element; ROS, reactive oxygen species; RXR, retinoid X receptor; TNF-α, tumor necrosis factor α.

Fig 2. PPARγ and LXR signaling in macrophages results in resistance or susceptibility to pathogens.

Infection with different pathogens can result in activation of PPARγ and LXR. Pathways regulated by these NRs and their impact on the host (mediating a resistant or susceptible phenotype) and pathogen (altered growth specified by ↑ or ↓) are indicated. Solid arrows indicate NR-mediated mechanisms between macrophage responses and effect on pathogen and/or disease. The dashed arrow indicates correlative links between NR-mediated macrophage responses and disease. CGD, chronic granulomatous disease; GI, gastrointestinal; LXR, liver X receptor; MRSA, methicillin-resistant Staphylococcus aureus; NAD, nicotinamide adenine dinucleotide; NO, nitric oxide; PPARγ, peroxisome proliferator-activated receptor gamma; RSV, respiratory syncytial virus.

Fig 3. Newly described NR activity linked to macrophage responses to infectious diseases.

Links between certain NRs and macrophage responses to infectious pathogens have recently emerged and are highlighted here. Overall, the NRs described here appear to aid in control of inflammatory responses of macrophages, leading to resistance against many diseases. The xenobiotic receptor PXR also induces efflux of antimicrobial drugs from macrophages, leading to dangerous side effects and susceptibility to Mycobacterium tuberculosis and HIV. Although no clear mechanistic links between these NRs and infection have been described, future study into these and other NRs may reveal novel targets for host-directed therapeutic development against infectious diseases. ERR, estrogen related receptor; FXR, farnesoid X receptor; IFN-γ, Interferon-γ; IL-10, interleukin 10; mROS, mitochondrial reactive oxygen species; NLRP3, NLR Family Pyrin Domain Containing 3; NR, nuclear receptor; NR4A, nuclear receptor 4A; PPARγ, peroxisome proliferator-activated receptor gamma; PXR, pregnane X receptor; VDR, vitamin D receptor.