Exosomes Derived From Septic Mouse Serum Modulate Immune Responses via Exosome-Associated Cytokines

Abstract

Sepsis is a life-threatening condition caused by an immune response triggered by infection, and highly elevated cytokine/chemokine levels in the blood play crucial roles in the progression of sepsis. Serum exosomes are nanovesicles that have multiple biological functions, playing roles in antigen presentation, intercellular signal communication, inflammatory response and immune surveillance. However, the biological functions and related molecular bases remain to be elucidated. In this study, we investigated the profiles of cytokines/chemokines harbored in the exosomes of septic mice and explored the mechanisms of immunomodulation on T cells treated with exosomes harvested from septic mice. Blood cytokines/chemokines existed in both the soluble form and in the insoluble exosomal form; the profiles of the cytokines/chemokines in these two forms displayed different dynamics in the blood of mice challenged with LPS. Exosomes from septic mice induced the differentiation of Th1/Th2 cells, which was blocked by specific antibodies targeting IL-12 and IL-4. In addition, these exosomes significantly augmented the proliferation and migration of T lymphocytes. Furthermore, preadministration of exosomes by intravenous injection restrained the inflammatory response, attenuated lung and liver tissue damage, and prolonged the survival of cecal ligation and puncture (CLP) mice. Our results indicate that exosomes enriched with cytokines/chemokines play critical roles in T cell differentiation, proliferation and chemotaxis during the sepsis process and have a protective effect on cecal ligation and puncture (CLP) mice. Thus, these findings not only strengthen our understanding of the role of sepsis via exosomes but also provide potential targets for therapeutic applications.

Exosomal miRNAs in tumor microenvironment

“…Exosomes are involved in the biology of many diseases. Exosomes can regulate the immune response and inflammation, possibly through transfer and presentation of antigen peptides, to induce expression of inflammatory genes in recipient cells [64,65]. In metabolism and cardiovascular diseases, exosomes induce metabolic disorders in adipocytes and islet cells [66,67].…”

“…Conversely, a reciprocal exosomal miRNAs exchange from the stroma to cancer cells also modulates cancer progression. For example, CAFs-derived exosomal miR-148b in the matrix surrounding endometrial cancer can up-regulate DNMT1, leading to changes in EMT-related molecules like E-cadherin, N-cadherin, vimentin, and fibronectin and promoting cancer cell metastasis [65]. CAFs are resistant to cisplatin and deliver exosomal miR-196a, which binds to target CDKN1B and ING5, mediates the expressions of p27, CDK2, CDK4, Cyclin D1 and Cyclin E1 and thus induces cisplatin resistance to cancer cells [115].…”

Exosomes in Sepsis

“…Exosomes play a significant role in sepsis, since they can induce inflammation by activating cells with their contents (6). The number of exosomes was elevated in the sera of mice after the injection of LPS, a major bacterial component which induces endotoxemia -a syndrome that recapitulates most aspects of sepsis (11). In vitro experiments also showed that the amount of exosomes was increased in the media of LPS-challenged cells (12).…”

“…Sepsis patients show increased levels of various cytokines, both proinflammatory and immunosuppressive, locally, and systemically (15,16). Protein array analysis of exosomes from septic mice showed that some of the pro-inflammatory cytokines, such as IL-1β, IL-2, IL-6, and TNF-α, started to augment in the early phase followed by other pro-inflammatory cytokines, including IL-12, IL-15, IL-17, and IFN-γ, in the late phase (11). Consistent with sepsis pathology, anti-inflammatory cytokines, IL-4 and IL-10, contained in exosomes of sepsis mice increased in the late phase (11).…”

“…Protein array analysis of exosomes from septic mice showed that some of the pro-inflammatory cytokines, such as IL-1β, IL-2, IL-6, and TNF-α, started to augment in the early phase followed by other pro-inflammatory cytokines, including IL-12, IL-15, IL-17, and IFN-γ, in the late phase (11). Consistent with sepsis pathology, anti-inflammatory cytokines, IL-4 and IL-10, contained in exosomes of sepsis mice increased in the late phase (11). Moreover, GW4869, exosome inhibitor, significantly attenuated the levels of systemic cytokines of mice subjected to LPS-injection or CLP (14).…”