Alarming Cargo: The Role of Exosomes in Trauma-Induced Inflammation

Abstract

Severe polytraumatic injury initiates a robust immune response. Broad immune dysfunction in patients with such injuries has been well-documented; however, early biomarkers of immune dysfunction post-injury, which are critical for comprehensive intervention and can predict the clinical course of patients, have not been reported. Current circulating markers such as IL-6 and IL-10 are broad, non-specific, and lag behind the clinical course of patients. General blockade of the inflammatory response is detrimental to patients, as a certain degree of regulated inflammation is critical and necessary following trauma. Exosomes, small membrane-bound extracellular vesicles, found in a variety of biofluids, carry within them a complex functional cargo, comprised of coding and non-coding RNAs, proteins, and metabolites. Composition of circulating exosomal cargo is modulated by changes in the intra- and extracellular microenvironment, thereby serving as a homeostasis sensor. With its extensively documented involvement in immune regulation in multiple pathologies, study of exosomal cargo in polytrauma patients can provide critical insights on trauma-specific, temporal immune dysregulation, with tremendous potential to serve as unique biomarkers and therapeutic targets for timely and precise intervention.

Keywords: exosomes; extracellular vesicles; inflammation; intercellular communication; trauma.

Figure 1

Exosome biogenesis. (1) Invagination of the plasma membrane of the cell collects extracellular material and generates a membrane bound endosome within the cell which retains plasma membrane proteins such as tetraspanins. (2) Golgi network packaging and transport of cellular material to the endosome. (3) Endosomal sorting complex required for transport (ESCRT) machinery packaging of biomaterial. (4) Invagination of the endosome forms intraluminal vesicles (ILVs). The collection of ILVs within an endosome forms a multivesicular body (MVB). There is cellular content from the cytosol contained within the ILVs as a result of microautophagy. (5) Trafficking of the MVB to the lysosome. MVB fusion with the lysosome results in ILV degradation. (6) Exosomes are released when the ILVs are released following MVB fusion with the plasma membrane. (7) Close-up of exosomes at release, with tetraspanins and bioactive cargo. (8) Budding of the plasma membrane forming microvesicles. These extracellular vesicles (EVs) are distinguishable from exosomes by nature of their biogenesis, and size. (9) Recycling of early endosome content to the plasma membrane.

Figure 2

Response to traumatic injury. The three phases following injury are identified by the arrows at the top of the timeline: survival, hyperinflammation, and repair. The longer the hyperinflammation phase is extended, the more delayed the initiation of the repair phase, contributing to late term healing complications. The text beneath the response phase arrows lists various complications associated with increased mortality during the course of the body’s response to trauma—the majority of these conditions after the survival phase are caused by or related to inflammation. The dotted green line shows a “normal” appropriate, restrained inflammatory response that begins to resolve a few days after injury. The red curve represents non-survival—patients that will expire immediately following injury or within the earliest phases of care due to insurmountable injuries and exsanguination. These patients will fail to survive long enough to amount a robust inflammatory response. The orange curve represents patients that will be lost in the first few days of care, usually due to complications related to resuscitation, including ischemic reperfusion injury (IRI), or injury severity, especially in the setting of traumatic brain injury (TBI). The black curve encompasses the patient population that will experience delayed trauma-associated hyperinflammation-induced complications, beginning several days after the initial injury. Dysregulation of the inflammatory response or further insults will cause a patient to deviate from normal recovery, making them more susceptible to the development of systemic inflammatory response syndrome (SIRS), or infection that may cause further complications or death.

Figure 3

Inflammatory cytokines and the self-propagating trauma cycle. This diagram is a simplified representation of the complex web of pro-inflammatory cytokines and how continued activation leads to further tissue damage. The release of damage associated molecular patterns (DAMPs), platelets, and thrombin in response to injury activates macrophages and endothelial cells to mount a response. Cytokines, including interleukins (IL), and tumor necrosis factor (TNF)-α are key early messengers in the inflammatory response, acting to activate natural killer (NK) cells, macrophages, neutrophils, and hepatocytes. Hyperinflammation from an unrestrained response further contributes to tissue damage, engaging the inflammatory response again.