Exosomal mediators in sepsis and inflammatory organ injury: unraveling the role of exosomes in intercellular crosstalk and organ dysfunction

Abstract

Sepsis, a severe systemic inflammatory response to infection, remains a leading cause of morbidity and mortality worldwide. Exosomes, as mediators of intercellular communication, play a pivotal role in the pathogenesis of sepsis through modulating immune responses, metabolic reprogramming, coagulopathy, and organ dysfunction. This review highlights the emerging significance of exosomes in these processes. Initially, it provides an in-depth insight into exosome biogenesis and characterization, laying the groundwork for understanding their diverse and intricate functions. Subsequently, it explores the regulatory roles of exosomes in various immune cells such as neutrophils, macrophages, dendritic cells, T cells, and B cells. This analysis elucidates how exosomes are pivotal in modulating immune responses, thus contributing to the complexity of sepsis pathophysiology. Additionally, this review delves into the role of exosomes in the regulation of metabolism and subsequent organ dysfunction in sepsis. It also establishes a connection between exosomes and the coagulation cascade, which affects endothelial integrity and promotes thrombogenesis in sepsis. Moreover, the review discusses the dual role of exosomes in the progression and resolution of sepsis, exploring their complex involvement in inflammation and healing processes. Furthermore, it underscores their potential as biomarkers and therapeutic targets. Understanding these mechanisms presents new opportunities for novel interventions to mitigate the severe outcomes of sepsis, emphasizing the therapeutic promise of exosome research in critical care settings.

Keywords: Biomarkers; Exosomes; Inflammation; Intercellular crosstalk; Sepsis.

Fig. 1

Mechanisms of exosome regulation of immunity in sepsis. Exosomes derived from immune cells are instrumental in orchestrating a balance between immunoregulatory and autoimmune responses within a complex network of immune interactions. These vesicles are rich in bioactive molecules and play key roles in the inflammatory process by guiding PMN recruitment and migration, supporting the innate immune response, and influencing macrophage polarization towards either pro-inflammatory M1 or anti-inflammatory M2 states, thereby shaping the progression of inflammation. DC-derived exosomes are crucial in engaging memory T cells, triggering their differentiation into Th1, Th2, or Treg cells and fostering a proliferative response essential for robust immunity. Additionally, these exosomes enhance adaptive immunity by aiding in B cell maturation and improving antigen presentation. Simultaneously, they significantly impact the activation and proliferation of CD8⁺ T cells, highlighting their extensive involvement in modulating immune responses, particularly during sepsis. PMN neutrophil, DC dendritic cell, NET neutrophil extracellular traps, Th1 type 1 helper T cells, Th2 type 2 helper T cells, Ab antibody

Fig. 2

Exosomes regulation of sepsis-induced coagulopathy. Exosomes intricately regulate the balance between immune and coagulation responses in the pathophysiology of sepsis-induced coagulopathy. Macrophage-derived exosomes directly exert procoagulant activity, thereby initiating the coagulation cascade. Furthermore, these vesicles significantly influence neutrophil (PMN) recruitment and neutrophil extracellular traps (NETs), effectively linking inflammatory and coagulation pathways. Additionally, platelet-derived exosomes enhance both coagulation and inflammation, which may potentially lead to disseminated intravascular coagulation (DIC) and subsequent organ damage. Endothelial dysfunction can be notably impacted by exosomal signals from various cells, thereby contributing to ongoing inflammation and coagulation. Conversely, exosomes from endothelial progenitor cells (EPCs) play a crucial role in facilitating vascular repair and reducing endothelial permeability, effectively countering the vascular effects of sepsis. This underscores the significant role of exosomes in the development of coagulopathy during sepsis. PS phosphatidylserine, TF tissue factor, HMGB1 high mobility group box 1, ARA arachidonic acid, IL-10 interleukin 10, MMP9 matrix metallopeptidase 9

Fig. 3

Exosome-mediated intercellular crosstalk in organ dysfunction. Exosomes mediate crucial intercellular communication between releasing and recipient cells, playing a significant role in the progression of sepsis-related organ dysfunction. a In acute lung injury, epithelial cells play a crucial role by releasing exosomes abundant in proteins and miRNAs, which induce macrophages to polarize towards the M1 phenotype, amplifying pulmonary inflammation. On the other hand, M1 macrophage-derived exosomal APN/CD13 and TNF exacerbate lung injury by promoting programmed cell death in lung epithelial cells. b In acute liver injury, hepatocytes release exosomes containing miR-192-5p, prompting macrophages to adopt the M1 phenotype. This polarization leads to the release of inflammatory mediators like iNOS, IL-6, and TNF-α into the hepatic microenvironment, worsening hepatic cell dysfunction. Additionally, exosomes from M1 macrophages containing miR-103-3p promote the proliferation and activation of hepatic stellate cells, further contributing to liver injury. c In acute cardiac dysfunction, exosomes from M1 macrophages containing miR-155 inhibit fibroblast proliferation, thus contributing to cardiac damage. Conversely, exosomes from M2 macrophages containing miR-148a suppress inflammasomes, reducing myocardial injury. MSCs further protect the heart by releasing exosomes laden with miR-22 and miR-221, which counteract cardiomyocyte apoptosis. d In acute kidney injury, tubular epithelial cells damaged by oxidative stress secrete exosomes with miR-19b-3p and miR-23a, inducing macrophages to polarize into the M1 phenotype. This exacerbates renal inflammation and contributes to the progression of kidney damage. APN/CD13 aminopeptidase N, TNF tumor necrosis factor, miRNAs microRNAs, M1 type 1 macrophage, M2 type 2 macrophage, iNOS inducible nitric oxide synthase, IL-6 interleukin 6, TNF-α tumor necrosis factor-α, MSCs mesenchymal stem cells, CASP3 caspase-3, PDGF platelet-derived growth factor, CCL2 C-C motif chemokine ligand 2