Immunology: Current Research
Open Access

Exosomes; Immune regulation; Intercellular communication; Immunomodulation; Biomarkers; Therapeutics

Introduction

The immune system is a complex network of cells, tissues, and molecules that collectively defend the body against pathogens and maintain tissue homeostasis. Central to this defense mechanism is the ability of immune cells to communicate with each other, coordinating their responses to various stimuli [1]. In recent years, exosomes have emerged as key players in intercellular communication, facilitating the transfer of bioactive molecules between cells and modulating diverse physiological and pathological processes. Exosomes, small extracellular vesicles ranging from 30 to 150 nm in diameter, are generated through the endocytic pathway and released into the extracellular environment upon fusion of multivesicular bodies (MVBs) with the plasma membrane [2]. These nanoscale vesicles carry a cargo comprising proteins, lipids, nucleic acids, and metabolites, which they deliver to recipient cells, thereby influencing their phenotype and function.

Biogenesis and composition of exosomes

Exosomes originate from the endosomal system, where intraluminal vesicles (ILVs) are formed within MVBs through inward budding of the endosomal membrane. The biogenesis of exosomes is tightly regulated by a complex interplay of molecular machinery, including the endosomal sorting complexes required for transport (ESCRT) machinery, lipid raft microdomains, and various Rab proteins [3]. Following their formation, MVBs can either fuse with lysosomes for degradation or with the plasma membrane for exosome release. The molecular composition of exosomes reflects their cellular origin and physiological state, with specific proteins, lipids, and nucleic acids selectively sorted into these vesicles. Common protein markers of exosomes include tetraspanins (CD9, CD63, CD81), heat shock proteins (HSP70, HSP90), and membrane transport and fusion proteins (Alix, TSG101). Moreover, exosomes are enriched in certain lipid species, such as cholesterol, sphingomyelin, and ceramide, which contribute to their stability and membrane curvature [4]. Importantly, exosomes also encapsulate various RNA species, including microRNAs (miRNAs), messenger RNAs (mRNAs), and long non-coding RNAs (lncRNAs), which can be transferred to recipient cells and regulate gene expression.

Exosomes in immune regulation

Exosomes play a pivotal role in modulating immune responses by regulating the function of immune cells and influencing inflammatory processes. These vesicles are secreted by a wide range of immune cells, including dendritic cells (DCs), macrophages, T cells, B cells, and natural killer (NK) cells, and can act on both neighboring and distant cells to orchestrate immune reactions. One of the key mechanisms by which exosomes modulate immune responses is through antigen presentation and T cell activation [5,6]. DC-derived exosomes, loaded with major histocompatibility complex (MHC) molecules and co-stimulatory molecules, can stimulate antigen-specific T cell responses and promote T cell activation and proliferation. Moreover, exosomes released by activated T cells can amplify immune responses by delivering cytokines and effector molecules to recipient cells. Additionally, exosomes derived from regulatory T cells (Tregs) and mesenchymal stem cells (MSCs) have immunosuppressive properties and can inhibit T cell proliferation and effector functions, thus contributing to immune tolerance and homeostasis.

In addition to their effects on T cells, exosomes also regulate the function of other immune cells, including B cells, NK cells, and macrophages. B cell-derived exosomes can modulate antibody production and antigen presentation, thereby influencing humoral immune responses [7]. NK cell-derived exosomes exhibit cytotoxic activity against target cells and regulate NK cell function and differentiation. Furthermore, exosomes released by macrophages play a crucial role in inflammation and tissue remodeling by delivering pro-inflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs) to target cells. Collectively, these findings underscore the diverse roles of exosomes in immune regulation and highlight their potential as therapeutic targets for immune-related disorders.

Exosome-Mediated crosstalk in inflammatory diseases

Dysregulation of exosome-mediated immune regulation has been implicated in various inflammatory diseases, including autoimmune disorders, infectious diseases, and cancer. In autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, aberrant secretion of exosomes by immune cells contributes to the breakdown of immune tolerance and the perpetuation of chronic inflammation. Similarly, in infectious diseases caused by viruses, bacteria, or parasites, pathogen-derived exosomes can modulate host immune responses and promote immune evasion and disease progression. Moreover, tumor-derived exosomes play a crucial role in cancer immune evasion by suppressing anti-tumor immune responses and promoting tumor growth, metastasis, and drug resistance [8]. Understanding the molecular mechanisms underlying exosome-mediated crosstalk in inflammatory diseases is essential for the development of novel diagnostic and therapeutic strategies targeting exosome biogenesis, secretion, and function.

Clinical implications and future perspectives

Exosomes hold great promise as diagnostic biomarkers and therapeutic targets for a wide range of immune-related disorders. Their presence in various biological fluids, including blood, urine, and saliva, makes them attractive candidates for non-invasive biomarker discovery and disease monitoring. Indeed, alterations in exosome cargo composition have been observed in numerous diseases, suggesting their potential utility as disease-specific biomarkers. Furthermore, exosomes can be engineered to deliver therapeutic payloads, such as drugs, small interfering RNAs (siRNAs), and CRISPR/Cas9 gene editing tools, to target cells with high specificity. Several preclinical and clinical studies have demonstrated the feasibility and efficacy of exosome-based therapeutics for the treatment of cancer, infectious diseases, and inflammatory disorders. However, several challenges remain to be addressed, including standardization of isolation and characterization methods, optimization of loading and delivery strategies, and elucidation of the long-term safety and efficacy of exosome-based therapies. Despite these challenges, the rapid advances in exosome research hold promise for revolutionizing the diagnosis and treatment of immune-related diseases in the near future.

Conclusion

In conclusion, exosomes play a multifaceted role in immune regulation, acting as mediators of intercellular communication and modulators of immune responses. Understanding the mechanisms underlying exosome-mediated immune regulation has significant implications for the development of novel therapeutic strategies for immune-related disorders. Further research is needed to elucidate the precise roles of exosomes in immune regulation and to harness their therapeutic potential effectively. By unraveling the intricate orchestra of exosome-mediated immune regulation, we can pave the way for innovative approaches to manipulate immune responses and promote health and well-being.

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