Exosomes in immunoregulation of chronic lung diseases

Abstract

Exosomes are nano-sized, membrane-bound vesicles released from cells that transport cargo including DNA, RNA, and proteins, between cells as a form of intercellular communication. In addition to their role in intercellular communication, exosomes are beginning to be appreciated as agents of immunoregulation that can modulate antigen presentation, immune activation, suppression, and surveillance. This article summarizes how these multifaceted functions of exosomes may promote development and/or progression of chronic inflammatory lung diseases including asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. The potential of exosomes as a novel therapeutic is also discussed.

Keywords: chronic lung diseases; exosomes; extracellular vesicles; immunoregulation; inflammation.

Figure 1

Graphical representation of various extracellular vesicles, their sizes, and related surface proteins. Color gradients indicate reported variability in size.

Figure 2

Homeostatic roles for exosomes and extracellular vesicles. (A) Injured tissue cells secrete exosomes and membrane particles that promote migration and differentiation of resident stem cells (progenitor cells). Tissue damage can also be “sensed” by resident or bone marrow stem cells, which can then secrete exosomes or membrane particles that may promote de-differentiation, cell-cycle progression, and tissue repair. (B) Exosomes are also important in the maturation process of various cell types, for example in the maturation of reticulocytes into erythrocytes through shedding of proteins and surface receptors by exosomes.

Figure 3

Exosomes in immune regulation. (A) Follicular dendritic cells (FDCs) gain MHC class II molecules from exosomes shed by B cells in the germinal centers. (B) Dendritic cells (DCs) can secrete exosomes bearing MHC molecules that potentially directly activate T cells. (C) Primed dendritic cells can secrete peptide-loaded MHC molecules that can be taken-up by naïve DCs which can then activate nearby T cells by displaying the loaded MHC molecule from exosome on its cell surface. Naïve DCs can also re-package the loaded MHC into new exosomes, thus amplifying the effect. (D) Both epithelial cells and DCs can secrete chemokine-containing exosomes which can recruit granulocytes and other inflammatory mediators.

Figure 4

(A) Classical mechanism of allergic asthma. An initial stimulus, such as pollen, is processed by dendritic cells and Th2 promoting cytokines released. Th2 polarized CD4⁺ T cells secrete a milieu of cytokines including IL-4 and IL-13, further promoting Th2 skewing of nearby CD4⁺ T cells. This stimulates plasma B cells to secrete IgE, a key mediator of allergic asthma. IgE induces histamine production by mast cells resulting in bronchoconstriction, which manifests clinically as wheezing or dyspnea. (B) Exosomes may have the potential to directly activate T cells and influence their activity, as well as mediate inflammation through leukotriene synthesis. Additionally, exosomes secreted by MDRCs may preferentially promote the development of T cell subsets, such as Th17 cells, which can drive inflammation. The inflammatory environment can promote bronchial epithelial cell production of exosomes, creating a vicious cycle of disease maintenance.