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Exosomes, not protein or lipids, in mesenteric lymph activate inflammation: Unlocking the mystery of post-shock
Mitsuaki Kojima1, Joao Antonio Gimenes-Junior, Simone Langness
1From the Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery (M.K., J.A.G.-J., S.L., K.M., O.L.-G., B.E., T.W.C., R.C.), University of California San Diego Health Sciences, San Diego, California.
Background:
Previous studies have shown that mesenteric lymph (ML) has a crucial role in driving the systemic inflammatory response after trauma/hemorrhagic shock (T/HS). The specific mediators in the ML that contribute to its biological activity remain unclear despite decades of study. Exosomes are extracellular vesicles that are shed into body fluids such as serum and urine that can mediate intercellular communication. We hypothesized that exosomes are present in the ML after trauma/shock and are responsible for the biological activity of ML.
Methods:
Male rats underwent cannulation of the vessels and mesenteric lymph duct. T/HS was induced by laparotomy and 60 minutes of HS (mean arterial pressure, 35 mmHg), followed by resuscitation. The ML was collected during three distinct time periods (pre-shock, shock, and resuscitation phase) and subsequently separated into exosome and supernatant fractions. Exosomes were characterized by electron microscope, nanoparticle tracking analysis, and immunoblotting. The biological activity of exosomes and supernatant of ML were characterized using a monocyte NF-κB reporter assay and by measuring macrophage intracellular TNF-α production.
Results:
Exosomes were identified in ML by size and expression of the exosome markers CD63 and HSP70. The number of exosomes present in the ML was 2-fold increased during shock and 4-fold decreased in resuscitation phase compared to pre-shock. However, biological activity of exosomes isolated during the resuscitation phase was markedly increased and caused an 8-fold increase in monocyte NF-κB activation compared to supernatant. Macrophage TNF-α production was also increased after exposure to exosomes harvested in the resuscitation phase. The ML supernatant fraction had no effect on TNF-α production during any phase.
Conclusions:
Our findings show that exosomes, and not the liquid fraction of ML, are the major component triggering inflammatory responses in monocytes and macrophages after experimental T/HS.
Insights
Mesenteric lymph exosomes drive inflammation after trauma and shock. These extracellular vesicles, not the lymph fluid, activate monocytes and macrophages, revealing key mediators of the systemic inflammatory response.
Area of Science:
- Trauma and hemorrhagic shock research
- Extracellular vesicle biology
- Immunology and inflammation
Background:
- Mesenteric lymph (ML) plays a key role in systemic inflammation post-trauma/hemorrhagic shock (T/HS).
- The specific inflammatory mediators within ML remain unidentified.
- Exosomes, involved in intercellular communication, are hypothesized to be the active components in ML.
Purpose of the Study:
- To investigate the presence and role of exosomes in ML following T/HS.
- To determine if ML exosomes are responsible for the biological activity of ML.
Main Methods:
- T/HS was induced in male rats, with ML collected during pre-shock, shock, and resuscitation phases.
- ML was fractionated into exosomes and supernatant.
- Exosomes were characterized, and biological activity was assessed using monocyte NF-κB reporter assays and macrophage TNF-α production measurements.
Main Results:
- Exosomes were identified in ML, with numbers increasing during shock and decreasing during resuscitation.
- Exosomes isolated during resuscitation significantly increased monocyte NF-κB activation (8-fold).
- Exosomes from the resuscitation phase elevated macrophage TNF-α production, while ML supernatant had no effect.
Conclusions:
- Exosomes, not the liquid supernatant, are the primary drivers of inflammatory responses in monocytes and macrophages after experimental T/HS.
- This study identifies exosomes in ML as key mediators of post-T/HS inflammation.
