Abstract
Cirrhosis is associated with dysregulated immune cell activation and immune dysfunction. These conditions modify gut flora, facilitate bacterial translocation, and increase susceptibility to bacterial peritonitis and consequent systemic infections by dramatically affecting long-term patient survival. Human amnion-derived mesenchymal stromal cells (hA-MSCs) exert immunomodulatory potential benefit, and have the ability to modulate their actions, especially in situations requiring immune activation through mechanisms not fully understood. In this study, we aimed to investigate, in vitro, the immunostimulant or immunosuppressive effects of hA-MSCs on cellular components of ascitic fluid obtained from cirrhotic patients with refractory ascites. We found that hA-MSCs viability is not affected by ascitic fluid and, interestingly, hA-MSCs diminished the pro-inflammatory cytokine production, and promoted anti-inflammatory M2 macrophage polarization. Moreover, we found that there was no simultaneous significant decrease in the M1-like component, allowing a continual phagocytosis activity of macrophages and NK cells to restore a physiological condition. These data highlight the plasticity of hA-MSCs’ immunomodulatory capacity, and pave the way to further understanding their role in conditions such as spontaneous bacterial peritonitis.Graphical abstract
Highlights
Chronic liver disease (CLD) is currently the 4th cause of death among people aged 45–64 years, and is responsible for 170,000 deaths per year in Europe, and is by far the leading indication for liver transplantation (LT) [1]
We evaluated whether and how the CD14+ monocytes present in ascitic fluid (AF) may differentiate towards an M1 or M2 macrophage profile during co-culture with Human amnion-derived mesenchymal stromal cells (hA-mesenchymal stromal cells (MSCs)) [31] and we further demonstrated that hAMSCs did favor the shift and maintenance from proinflammatory M1 macrophages toward an M2 state in vitro, as expected since M2-like polarization has been proposed in chronic parasitic, viral, or bacterial diseases [32]
The hA-MSCs cultured in Roswell Park Memorial Institute (RPMI) and in AF were routinely observed under contrast phase light microscope and compared morphologically
Summary
Chronic liver disease (CLD) is currently the 4th cause of death among people aged 45–64 years, and is responsible for 170,000 deaths per year in Europe, and is by far the leading indication for liver transplantation (LT) [1]. The microbiological characteristics of bacterial infections have changed due to an increase of multiresistant germs as a consequence of extended use of primary antibiotic prophylaxis, frequent hospitalizations, and greater use of invasive techniques [9] The bacteria and their products are able to activate the immune system with increased release of mediators such as NO, TNF-α, IL-6, and IL-1, able to induce the systemic inflammatory response syndrome, progression of which culminates in the multi-organ failure [10]. Cytokines are key components of the immune system, and systemic inflammation is associated with a decreased concentration of anti-inflammatory cytokines in the AF of cirrhotic patients [11] Another complication is represented by the so-called “immune paralysis” determined by a reduction of both HLA-DR antigen expression in monocytes and pro-inflammatory cytokine production. It has been shown that monocytes/macrophages obtained from patients with bacterial DNA have an increased expression of IL-6 and TNF-α after LPS stimulation [14]
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