Interleukin-10 controls the protective effects of circulating microparticles from patients with septic shock on tissue-engineered vascular media

Abstract

During sepsis, inflammation can be orchestrated by the interaction between circulating and vascular cells that, under activation, release MPs (microparticles). Previously, we reported that increased circulating MPs in patients with sepsis play a pivotal role in ex vivo vascular function suggesting that they are protective against vascular hyporeactivity. The present study was designed to investigate the effects of MPs from patients with sepsis on the contractile response of TEVM (tissue-engineered vascular media). TEVM that were composed only of a media layer were produced by tissue engineering from human arterial SMCs (smooth muscle cells) isolated from umbilical cords. TEVM was incubated with MPs isolated from whole blood of 16 patients with sepsis. TEVM were incubated for 24 h with MPs and used for the study of vascular contraction, direct measurements of NO and O2- (superoxide anion) production by EPR and quantification of mRNA cytokine expression. MPs from patients with sepsis increased contraction induced by histamine in TEVM. This effect was not associated with inflammation, neither linked to the activation of NF-κB (nuclear factor κB) pathway nor to the increase in iNOS (inducible NO synthase) and COX (cyclo-oxygenase)-2 expression. In contrast, mRNA expression of IL (interleukin)-10 was enhanced. Then, we investigated the effect of IL-10 on vascular hyporeactivity induced by LPS (lipopolysaccharide). Although IL-10 treatment did not modify the contractile response in TEVM by itself, this interleukin restored contraction in LPS-treated TEVM. In addition, IL-10 treatment both prevented vascular hyporeactivity induced by LPS injection in mice and improved survival of LPS-injected mice. These findings show an association between the capacity of MPs from patients with sepsis to restore vascular hyporeactivity induced by LPS and their ability to increase IL-10 in the tissue-engineered blood vessel model.

Dynamic microvesicle release and clearance within the cardiovascular system: triggers and mechanisms

“…Interestingly, the positive-feedback loop between MVs and inflammation may not be so clear cut, as MVs from patients with sepsis have been shown to enhance aortic contraction in mice and it has been proposed they may play a protective role by reversing the fall in peripheral resistance and hypotension seen in severe sepsis [71] as well as promoting the release of IL-10 [75]. MVs, particularly those derived from granulocytes, have also been noted to have anti-inflammatory properties [75][76][77][78]. Together, these studies suggest that pro-inflammatory cytokines are potent triggers for MV release and the response can be modified with targeted cytokine therapies.…”

Microparticles: markers and mediators of sepsis-induced microvascular dysfunction, immunosuppression, and AKI

“…We have demonstrated that administration of bone marrow-derived mesenchymal stem cells (BMSCs) to mice shortly (up to 1h) after the induction of sepsis increases survival and improves organ dysfunction, including AKI, by immunomodulatory effects: monocytes and/or macrophages from septic mice treated with BMSCs release more interleukin-10 (IL-10), and the beneficial effects of BMSCs were eliminated by macrophage depletion or pretreatment with antibodies specific for IL-10 [ 86 ]. Interestingly, a study by another group demonstrated that MPs derived from plasma of septic patients increases mRNA expression of IL-10 in engineered vascular tissue and increases contraction of these vascular cells induced by histamine [ 87 ]. The paracrine effects of mesenchymal stem cells (MSCs) during AKI may be driven, at least in part, by a horizontal transfer of mRNA and microRNAs through MPs.…”

Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment

“…[60][61][62][63] Specifically, in sepsis and subsequent organ damage, endogenous EVs have been implicated as critical immunomodulatory factors that can regulate inflammation, [64][65][66][67][68][69][70][71][72][73] coagulation, [74][75][76][77][78][79][80][81][82] apoptosis, [83] and vascular dysfunction. [69,[84][85][86][87][88] The ability of EVs to trigger, amplify, and sometimes suppress immune responses during disease can be attributed to the presence of distinct membranous proteins or lipids (e.g., phosphatidylserine (PS), integrins, major histocompatibility complexes) and to differential lu-minal cargo (e.g., miRNAs, proteins). [30,89] There is much research dissecting these attributes and the mechanisms through which they work, as it can prove not only beneficial in the development of an EV therapeutic but also in clarifying the complex pathophysiology of sepsis.…”

“…[95] When applied to engineered vascular constructs comprising human arterial smooth muscle cells, EVs from septic human patients were able to increase the expression of IL-10 and consequently reverse LPS-induced hyporeactivity and reduce oxidative stress. [86] Endogenous EVs can also serve as sepsis biomarkers to inform treatment strategy and timing, especially in critically ill patients. [100] As an example, in human septic patients, Dakhlallah et al showed that circulating EVs had significantly higher loads of DNA methyltransferase (DNMT) mRNA, which regulates gene expression.…”