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International audience; Il‐17A is considered to guide liver inflammation and fibrosis. Using human liver slice culture, we aim to study whether IL‐17A is capable of influencing the fibrogenesis, but also, to look into lymphatic immune cell composition, secreting IL‐17A. Using human liver samples (F0‐F4) and blood samples, collected after partial hepatectomy due to different pathologies, we analyzed IL‐17A secretion and immune cell profile. Liver tissue was used for primary culture of human liver slices, followed by subsequent cytokine stimulation and analysis by Elisa of fibrotic markers. The Huh7.5.1 cell line was used for SeaHorse and WB analysis. IL‐17A concentration in human liver tissue was significantly higher in the early fibrotic stage compared with the advanced stage. Th17 T cells and, to a lesser extent, MAIT cells are the main sources of IL‐17A in both compartments, liver and blood. Moreover, the presence of liver Th17IL‐ 17A+INFγ+ cells were detected. IL‐17A stimulation of human liver slices increases the expression of profibrotic markers. Stimulation by IL‐17A+TGF‐β1 removes the reserve respiratory capacity in Huh7.5.1 cells, while RA addition is capable to restore it and to reverse the expression of LC3II/LC3I ratio. IL‐17A, secreted by Th17 and MAIT cells, induce the expression of pro‐fibrotic markers. However, the level of hepatic IL‐17A secretion is probably more related to the underlying pathologies that cause fibrosis rather than to the mechanism of fibrosis itself. There is also a terrain of communication between IL‐17A and retinoic acid in the liver, that should be investigated.

The aim of this clinical trial was to control the cytokine storm by administering mesenchymal stem cells (MSCs) to critically-ill COVID-19 patients, to evaluate the healing effect, and to systematically investigate how the treatment works. Patients with moderate and critical COVID-19 clinical manifestations were separated as Group 1 (moderate cases, n = 10, treated conventionally), Group 2 (critical cases, n = 10, treated conventionally), and Group 3 (critical cases, n = 10, treated conventionally plus MSCs transplantation therapy of three consecutive doses on treatment days 0, 3, and 6, (as 3 × 106 cells/kg, intravenously). The treatment mechanism of action was investigated with evaluation markers of the cytokine storm, via biochemical parameters, levels of proinflammatory and anti-inflammatory cytokines, analyses of tissue regeneration via the levels of growth factors, apoptosis markers, chemokines, matrix metalloproteinases, and granzyme-B, and by the assessment of the immunomodulatory effects via total oxidant/antioxidant status markers and the levels of lymphocyte subsets. In the assessment of the overall mortality rates of all the cases, six patients in Group-2 and three patients in Group-3 died, and there was no loss in Group-1. Proinflammatory cytokines IFNγ, IL-6, IL-17A, IL-2, IL-12, anti-inflammatory cytokines IL-10, IL-13, IL-1ra, and growth factors TGF-β, VEGF, KGF, and NGF levels were found to be significant in Group-3. When Group-2 and Group-3 were compared, serum ferritin, fibrinogen and CRP levels in Group-3 had significantly decreased. CD45 +, CD3 +, CD4 +, CD8 +, CD19 +, HLA-DR +, and CD16 + / CD56 + levels were evaluated. In the statistical comparison of the groups, significance was only determined in respect of neutrophils. The results demonstrated the positive systematic and cellular effects of MSCs application on critically ill COVID-19 patients in a versatile way. This effect plays an important role in curing and reducing mortality in critically ill patients.