Intestinal Epithelium-Derived Luminally Released Extracellular Vesicles in Sepsis Exhibit the Ability to Suppress TNF-α and IL-17A Expression in Mucosal Inflammation

Abstract

Sepsis is a systemic inflammatory disorder induced by a dysregulated immune response to infection resulting in dysfunction of multiple critical organs, including the intestines. Previous studies have reported contrasting results regarding the abilities of exosomes circulating in the blood of sepsis mice and patients to either promote or suppress inflammation. Little is known about how the gut epithelial cell-derived exosomes released in the intestinal luminal space during sepsis affect mucosal inflammation. To study this question, we isolated extracellular vesicles (EVs) from intestinal lavage of septic mice. The EVs expressed typical exosomal (CD63 and CD9) and epithelial (EpCAM) markers, which were further increased by sepsis. Moreover, septic-EV injection into inflamed gut induced a significant reduction in the messaging of pro-inflammatory cytokines TNF-α and IL-17A. MicroRNA (miRNA) profiling and reverse transcription and quantitative polymerase chain reaction (RT-qPCR) revealed a sepsis-induced exosomal increase in multiple miRNAs, which putatively target TNF-α and IL-17A. These results imply that intestinal epithelial cell (IEC)-derived luminal EVs carry miRNAs that mitigate pro-inflammatory responses. Taken together, our study proposes a novel mechanism by which IEC EVs released during sepsis transfer regulatory miRNAs to cells, possibly contributing to the amelioration of gut inflammation.

Cellular and Exosomal Regulations of Sepsis-Induced Metabolic Alterations

“…Adipose tissue MSC-derived exosomes revealed to dampen septic inflammation and preserve kidney function by suppressing NF-κB p65, HIF-1α, and NADPH oxidase activity while upregulating SIRT1 and VEGF expressions [ 130 , 131 ]. In line with finding of regulatory function of exosomes, we have recently demonstrated the release of exosomes with altered miRNA composition into the intestinal lumen of septic mice [ 132 ]. These luminal exosomes showed a downregulation in messages of TNF-α and IL-17A in the inflamed intestinal tissues [ 132 ].…”

Exosome: The Regulator of the Immune System in Sepsis

“…The intestinal epithelial cell (IEC)-derived luminal EVs during sepsis inhibit the release of pro-inflammatory cytokines TNF- α and IL-17a through autocrine and paracrine ( Appiah et al, 2020 ). Exosomal PGE2 of IEC inhibit the activation of NKT and CD4+ T cells through cAMP/PKA-dependent pathway ( Deng et al, 2013 ).…”

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

“…Isolated exosomes from injured mice contained 360 differentially regulated miRNA and 190 unique miRNAs compared collections obtained from healthy controls. Injection of septic exosome preparations into the lumen of healthy ileum resulted in downregulation of TNF-α, IL-1β, IL-6, IL-17A, and IL-22, while treatment of inflamed ileum resulted in suppressed TNF-α and IL-17A activity, suggesting immunosuppressive activity [ 208 ]. Using a CLP model of sepsis, Wu et al identified six miRNAs, miR-16, miR-17, miR-20a, miR-20b, miR-26a, and miR-26b, with increased expression in serum exosomes eight hours after injury [ 209 ].…”

“…miR-27aHashemian et al, 2020[207] miR-19a, miR-21a, miR-22, miR-27a, miR-103-2, miR-107, miR-126a, miR-146b, miR-182, miR-200b, miR-203, miR-762 Appiah et al, 2020[208] miR-16, miR-17, miR-20a, miR-20b, miR-26a, miR-26bWu et al, 2013 [209] Upregulated: let-7b-5p, let-7c-5p, miR-122-5p, miR-1227-3p, miR-125b-5p, miR-1260a, miR-1262, miR-1267, miR-1290, miR-1298-5p, miR-1300, miR-140-3p, miR-16-5p, miR-1825, miR-192-5p, miR-193a-5p, miR-194-5p, miR-195-5p, miR-19a-3p, miR-25-3p, miR-30a-5p, miR-320a, miR-320b, miR-363-3p, miR-486-5p, miR-518d-3p, miR-519b-3p, miR-520d-3p, miR-532-3p, miR-548a-3p miR-548c-3p, miR-597-5p, miR-618, miR-625-3p, miR-636, miR-645, miR-720, miR-758-3p, miR-770-5p, miR-885-5p, miR-886-5p, miR-92a-3p, miR-99b-3pReal et al, 2018[210] Downregulated: miR-127-3p, miR-146a-5p, miR-151a-3p, miR-186-5p, miR-18a-5p, miR-199a-3p, miR-221-3p, miR-26a-5p, miR-28-5p, miR-301a-3p, miR-328, miR-331-3p, miR-335-5p, miR-339-3p, miR-340-5p, miR-340-3p, miR-590-3p, miR-628-5p, miR-744-5p miR-16, miR-17, miR-20a, miR-20b, miR-26a, miR-26bWu et al, 2013 [209] miR-27b, miR-125b, miR-21-5p, miR-30a-5p, miR-100-5p, miR-122-5p, miR-193a-5pReithmair et al, 2017 [211] lncRNA Hotairm1 Alkhateeb et al, 2020 [212] Protein NADPH, NO synthase Gambim et al, 2007 [213] IL-1β, IL-2, IL-6, TNF-α, IL-4, IL-10, CCL2, CCL3 Gao et al, 2019[214] …”