Gut Epithelial Cell-derived Exosomes Trigger Post-trauma Immune Dysfunction

ABSTRACT Introduction Exosomes are extracellular vesicles that act as endogenous mediators of the immune response. We have previously shown that exosomes released into mesenteric lymph (ML) following trauma/hemorrhagic shock (T/HS) induce pro-inflammatory cytokine production in macrophages and are involved in the pathogenesis of post-shock acute lung injury. However, the cellular origin of ML exosomes and their role in the post-trauma immune response remains unclear. We hypothesized that exosomes released from damaged-intestinal epithelial cells (IECs) contribute to post-trauma immune dysfunction by altering the function of dendritic cells (DCs), key regulators of the adaptive immunity. Methods Male rats underwent cannulation of the femoral artery, jugular vein and ML duct. T/HS was induced by laparotomy and 60 minutes of hemorrhagic shock followed by resuscitation. The ML was collected before (pre-shock) and after T/HS (post-T/HS) for isolation of exosomes. Surface epitopes of exosomes isolated from ML were assessed by flow cytometry to determine their cellular origin and phenotypic changes. The immunomodulatory effects of ML exosomes on DCs were assessed by Annexin V apoptosis assay, expression of costimulatory molecules and antigen-presenting capacity to lymphocytes. Results Exosomes isolated from ML highly expressed CD63 (exosome marker) and EpCAM (epithelial cell-specific marker), suggesting their derivation from IECs. The expression of immunomodulatory molecules such as MHC class II and Fas ligand on ML exosomes were significantly increased after T/HS. Co-incubation of DCs with exosomes isolated from ML after T/HS increased DC apoptosis 2-fold compared to pre-shock ML exosomes. Furthermore, post-T/HS ML exosomes significantly suppressed LPS-mediated expression of CD80 and CD86 on DCs as well as decreased their antigen-presenting capacity to induce lymphocytes proliferation. Conclusion Gut epithelial cells release immunomodulatory exosomes into the ML after T/HS and resuscitation. ML exosomes may be critical mediators of post-traumatic immunosuppression causing depletion and dysfunction of DCs. LEVEL of EVIDENCE V (Basic science) Scheduled to be presented at the 76th Annual Meeting of the American Association for the Surgery of Trauma, Baltimore, MD, September 15, 2017. The authors report no conflicts of interest Corresponding Author: Raul Coimbra MD, PhD, FACS, 200 W. Arbor Drive, #8896, San Diego, CA 92103-8896, Email: rcoimbra@ucsd.edu © 2017 Lippincott Williams & Wilkins, Inc.

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