Exogenous and Endogenous Dendritic Cell-Derived Exosomes: Lessons Learned for Immunotherapy and Disease Pathogenesis

Abstract

Immune therapeutic exosomes, derived exogenously from dendritic cells (DCs), the 'directors' of the immune response, are receiving favorable safety and tolerance profiles in phase I and II clinical trials for a growing number of inflammatory and neoplastic diseases. DC-derived exosomes (EXO), the focus of this review, can be custom tailored with immunoregulatory or immunostimulatory molecules for specific immune cell targeting. Moreover, the relative stability, small size and rapid uptake of EXO by recipient immune cells offer intriguing options for therapeutic purposes. This necessitates an in-depth understanding of mechanisms of EXO biogenesis, uptake and routing by recipient immune cells, as well as their in vivo biodistribution. Against this backdrop is recognition of endogenous exosomes, secreted by all cells, the molecular content of which is reflective of the metabolic state of these cells. In this regard, exosome biogenesis and secretion is regulated by cell stressors of chronic inflammation and tumorigenesis, including dysbiotic microbes, reactive oxygen species and DNA damage. Such cell stressors can promote premature senescence in young cells through the senescence associated secretory phenotype (SASP). Pathological exosomes of the SASP amplify inflammatory signaling in stressed cells in an autocrine fashion or promote inflammatory signaling to normal neighboring cells in paracrine, without the requirement of cell-to-cell contact. In summary, we review relevant lessons learned from the use of exogenous DC exosomes for immune therapy, as well as the pathogenic potential of endogenous DC exosomes.

Keywords: Porphyromonas gingivalis; SASP; dendritic cells; exosomes; immune senescence; periodontitis.

Figure 1

DC Exosome (Exo) Therapy for the Inflammatory Bone Disease Periodontitis. 1. TGFb-/IL-10 enriched exo (regDC exo) are released. 2. Exo injected into palatal gingiva interproximal at site of ligand induced PD. 3. Exo uptake by acceptor gingival DCs reduces DC maturation and alters cytokine profile; 4 and 5. Modulation of osteoclastogenic Th17 response by regDCexo.

Figure 2

Cellular Senescence due to Advanced Age and Cell Stressors: Role of Exosomes. Advanced age and canonical (e.g., doxorubicin) and non-canonical (e.g., P.gingivalis) cell stressors can provoke cellular senescence (CS). Premature CS can occur by exposure to X irradiation, doxorubicin, reactive oxygen species (ROS), and microbial CS stressors. Senolytic agents (e.g., rapamycin, metformin) can remove senescence cells. CS profiling identifies elevated SA-β-Gal, p16 INK4A, pAkt-1, p53, p21Waf1/Clip1, and soluble and exosomal SASP. Exosomes (exo, green circles) can transmit senescence to young cells in paracrine. CS is implicated in many age-related diseases such as periodontitis, type II diabetes and COVID-19.