Tackling exosome and nuclear receptor interaction: an emerging paradigm in the treatment of chronic diseases

Abstract

Nuclear receptors (NRs) function as crucial transcription factors in orchestrating essential functions within the realms of development, host defense, and homeostasis of body. NRs have garnered increased attention due to their potential as therapeutic targets, with drugs directed at NRs demonstrating significant efficacy in impeding chronic disease progression. Consequently, these pharmacological agents hold promise for the treatment and management of various diseases. Accumulating evidence emphasizes the regulatory role of exosome-derived microRNAs (miRNAs) in chronic inflammation, disease progression, and therapy resistance, primarily by modulating transcription factors, particularly NRs. By exploiting inflammatory pathways such as protein kinase B (Akt)/mammalian target of rapamycin (mTOR), nuclear factor kappa-B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and Wnt/β-catenin signaling, exosomes and NRs play a pivotal role in the panorama of development, physiology, and pathology. The internalization of exosomes modulates NRs and initiates diverse autocrine or paracrine signaling cascades, influencing various processes in recipient cells such as survival, proliferation, differentiation, metabolism, and cellular defense mechanisms. This comprehensive review meticulously examines the involvement of exosome-mediated NR regulation in the pathogenesis of chronic ailments, including atherosclerosis, cancer, diabetes, liver diseases, and respiratory conditions. Additionally, it elucidates the molecular intricacies of exosome-mediated communication between host and recipient cells via NRs, leading to immunomodulation. Furthermore, it outlines the implications of exosome-modulated NR pathways in the prophylaxis of chronic inflammation, delineates current limitations, and provides insights into future perspectives. This review also presents existing evidence on the role of exosomes and their components in the emergence of therapeutic resistance.

Keywords: Chronic diseases; Exosomes; Inflammation; MicroRNAs; Nuclear receptors.

Fig. 1

The interaction between exosomes and nuclear receptors (NRs) plays a crucial role in the development and progression of various chronic diseases. Exosomes can influence NRs by modulating their expression through the transfer of their contents, such as microRNAs (miRNAs). This alteration in NR expression affects downstream targets, contributing to the onset and progression of chronic diseases. Conversely, NRs can also regulate exosomes by modifying their secretion or altering their contents that are involved in patho-physiological conditions. AIDS acquired immune deficiency syndrome, CVDs cardiovascular diseases, HIV human immunodeficiency virus, NASH non-alcoholic steatohepatitis

Fig. 2

The pivotal role of nuclear receptors (NRs) in the etiology of chronic diseases. Aberrations in NR function are implicated in the initiation and progression of pathological states. NRs are crucial participants in the genesis and advancement of obesity, a condition primarily arising from lifestyle factors and associated inflammatory processes. Targeting NRs represents a significant avenue for obesity management. Administration of a methanol extract derived from Juniperus communis berries led to a reduction in weight and blood sugar levels in obese mice by upregulating PPARα, PPARγ and LXR. Moreover, deregulated expression of NRs has been implicated in the manifestation of various cancer hallmarks, including immune evasion, inflammation, replicative immortality, cell death evasion, invasion and metastasis, angiogenesis, mitochondrial dysfunction, evading growth suppressors, uncontrolled proliferation, and deregulated cellular energetics. Of note, the dual agonist of FXR and TGR5, INT-767, has exhibited therapeutic efficacy in countering non-alcoholic steatohepatitis (NASH) and combinatorial treatment involving RAR and LXR agonists, namely all-trans retinoic acid (ATRA) and TO-901317, respectively, has resulted in diminished replication of the HIV. AIDS acquired immune deficiency syndrome, HIV human immunodeficiency virus, PPAR peroxisome proliferator-activated receptor, LXR liver X receptor, ALT alanine transaminase, AST aspartate aminotransferase, MCD methionine-choline deficient, ABCA1 ATP-binding cassette A1, RAR retinoic acid receptor, TG triglycerides, RT reverse transcriptase

Fig. 3

Intercellular communication mediated by nuclear receptors (NRs) and exosomes in the pathophysiology of chronic diseases. The intricate network of intercellular communication facilitated by NRs and exosomes, elucidating their pivotal role in the etiology and progression of chronic diseases such as cancer, cardiovascular diseases (CVDs), chronic rhinosinusitis, diabetes, HIV/AIDS, non-alcoholic steatohepatitis (NASH), neurological diseases, and obesity. In the context of these chronic maladies, the interplay between NRs and exosomes emerges as a critical determinant, influencing disease development and trajectory. This figure illustrates the sources of exosomes and their reported target NRs across the spectrum of chronic diseases under consideration. A comprehensive understanding of these underlying mechanisms holds promise for identifying novel therapeutic targets, thereby paving the way for innovative treatment modalities for a myriad of chronic diseases. AIDS acquired immune deficiency syndrome, AR androgen receptor, BMSC bone marrow mesenchymal stem cell, EPC endothelial progenitor cell, ER estrogen receptor, HIV human immunodeficiency virus, hUC-MSC human umbilical cord mesenchymal cell, MDSC myeloid derived suppressor cell, PPAR peroxisome proliferator-activated receptor, PVAT perivascular adipose tissue, RORα retinoic acid receptor related orphan receptors alpha

Fig. 4

Interplay between exosomes and nuclear receptors (NRs) in regulating tumor microenvironment dynamics. This figure illustrates the intricate cross-talk between exosomes and NRs in cancer pathogenesis. Tumor-derived exosomes (TDEs) convey genetic material, including genes and non-coding RNAs, to dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs). This molecular cargo targets specific NRs, influencing the functionality of these immune cells and contributing to immune evasion. TDEs from HPV⁺ HNSCC cells downregulate PPARδ, activating macrophages and enhancing radiosensitivity. Chemoresistant cancer cells use exosomes to transfer miRNAs targeting NRs to wild-type cancer cells, conferring therapeutic resistance. Macrophage-derived exosomes regulate the AR/PHLPP/Akt/β-catenin axis in liver cancer cells, promoting invasion. Conversely, T cell-derived exosomes deliver miR-765, suppressing PLP2 in ERβ⁺ uterine corpus endometrial carcinoma (UCEC) cells, reducing proliferation, EMT, and inducing apoptosis. These findings highlight the communication network between cancer cells and stromal cells within the tumor microenvironment via exosomal/NR interactions, suggesting that manipulating NR expression through targeted interventions presents a promising therapeutic strategy for diverse cancer types. Akt protein kinase B, CDs chronic diseases, EMT epithelial to mesenchymal transition, ERβ estrogen receptor β, IFN-γ interferon-γ, miR microRNA, NF-κB nuclear factor kappa-B, PD-L1 programmed death-ligand 1, PHLPP PH domain and leucine rich repeat protein phosphatases, PLP2 proteolipid protein 2, PPAR peroxisome proliferator-activated receptor, PTEN phosphatase and tensin homolog, RORα retinoic acid receptor related orphan receptor alpha, SIRPα signal regulatory protein alpha, TGF-β transforming growth factor-β, TME tumor microenvironment

Fig. 5

Nuclear receptors (NRs) regulate exosome secretion or alter its contents to modulate signaling pathways associate with the development and progression of various chronic diseases. Upregulation of exosomal miR-19a and integrin-binding sialoprotein in the tumor microenvironment has been shown to foster osteoclast attraction leading to metastatic seeding. RXR agonist 6-OH-11-O-hydroxyphenanthrene (HP) treatment potentiated pioglitazone (PGZ)’s inhibition of mammosphere formation in breast cells, reducing stem cell markers. Moreover, LXR ligand (DDA) inducing DDA-sEVs, promoting DC maturation, Th1 polarization, and inhibiting melanoma growth in mice. Further, VDR agonist calcipotriol was shown to reduce M2 polarization in macrophages, downregulating exosomal SMAP-5, causing greater reduction in hepatic fibrosis. ApoE apolipoprotein E, CAIX carbonic anhydrase IX, DC dendritic cells, DDA dendrogenin A, ER estrogen receptor, HIF-1α hypoxia-inducible factors-1α, IL interleukin, LXR liver X receptor, miR microRNA, MMF mammosphere formation, MMP matrix metalloproteinase, NF-κB nuclear factor kappa-B, PPAR peroxisome proliferator-activated receptor, RXR retinoid X receptor, SMAP-5 smooth muscle cell-associated protein protein-5, SLUG snail family transcriptional repressor 2, VDR vitamin D receptor