Circulating Neutrophils of Nonalcoholic Steatohepatitis Patients Show an Activated Phenotype and Suppress T Lymphocytes Activity

Abstract

Neutrophils or PolyMorphonuclear Neutrophils (PMNs) are key effector cells of the innate immune system and thanks to their remarkable plasticity, establish a cross talk with T cells modulating their survival and effector functions. During Nonalcoholic Steatohepatitis (NASH), the advanced form of hepatic steatosis or NAFL, PMNs infiltrate liver tissue, becoming a histological feature of NASH. Our aim was to evaluate the frequency of PMNs in NAFL and NASH patients in order to understand how they modulate the activity of circulating CD4+ and CD8+ T cells. In our cohort of patients, NASH patients displayed a higher frequency of circulating PMNs that was strongly correlated to liver enzymes, grade of steatosis, inflammation and fibrosis, the hepatocellular ballooning, and NAFLD Activity Score (NAS). Furthermore, even if ex vivo, in both groups of patients, PMNs shared the same phenotype of resting cells, after 24 hours of coculture with autologous CD4+ and CD8+ T cells, PMNs of NASH patients acquired a more active phenotype, becoming able to strongly inhibit proliferation and activation of CD4+ and CD8+ T cells. The higher ability of PMNs of NASH patients in suppressing CD4+ and CD8+ T cells, over time, might contribute in reducing the immunological defense of liver tissue against damages thus taking part in the progression of the NAFL disease toward NASH.

Donor-derived regulatory dendritic cell infusion results in host cell cross-dressing and T cell subset changes in prospective living donor liver transplant recipients

“…Mechanisms by which adoptively transferred DCreg modulate host T cell reactivity in vivo continue to be elucidated 71 and include production of IL‐10 that drives Tregs, 72,73 expression of immune modulatory/inhibitory molecules such as PD‐L1/2, CTLA‐4, and ILT‐3/4, 74 and promotion of elevated levels of circulating lactate, that suppresses T cell glycolysis and immune reactivity 75 . The ability of DCregs to modulate anti‐donor T cell reactivity in prospective liver transplant recipients (the subjects of the present study) must be viewed in the context of liver disease‐induced defects/alterations in T cell functions 76‐80 that may underlie their inferior proliferative responses to allostimulation compared with those of healthy third party T cells (Figure 3). Although in the current study, DCreg did not cause any overall changes in host CD4 + and CD8 + T absolute cell numbers nor in CD4 + T cell phenotype between the time of their infusion and that of graft implantation, T‐bet hi Eomes hi memory CD8 + T cells declined and regulatory (CD25 hi CD127 − Foxp3 + ): effector T cell (T‐bet hi Eomes hi ) ratios increased significantly.…”

Neutrophil reverse migration from liver fuels neutrophilic inflammation to tissue injury in Nonalcoholic Steatohepatitis

“…Inflammatory response triggered by fat accumulation and associated lipotoxicity is a major contributor for progression from simple steatosis to NASH REF. Increased number of circulating myeloid cells, particularly neutrophils, have been reported in NAFLD/NASH 10 .Using a diet induced NASH zebrafish model that exhibits liver inflammation 14 and metabolic syndrome 26 after exposure to a high cholesterol diet (HCD) for 8 days (Suppl Fig. 1A), we first evaluated whether NASH larvae have increased number of myeloid cells.…”

“…Neutrophils have a doubleedge sword function being crucial for effective tissue repair but can also contribute for further damaged in case a dysfunctional response is triggered 8 . Neutrophils have a crucial role on NAFLD pathophysiology; with circulating neutrophils from patients with NASH exhibiting an activated and immunosuppressive phenotype 10 . Multiple reports have also found that circulating neutrophils in NASH have enhanced reactive oxygen species (ROS) production upon inflammatory stimulus, and undergo spontaneous NETs formation (i.e., NETosis) [10][11][12] , based on this evidence we decided to explore how neutrophilic inflammation to tissue injury was impacted in a NASH background.…”

The Effect of Probiotics (MCP® BCMC® Strains) on Hepatic Steatosis, Small Intestinal Mucosal Immune Function, and Intestinal Barrier in Patients with Non-Alcoholic Fatty Liver Disease

“…This finding was in agreement with other recent studies by Zhao et al (2021) and Ma et al (2016), which also found a selective loss of intrahepatic CD4+ T lymphocytes in both human and animal models due to lipid metabolism dysregulation [ 35 , 36 ]. Another new published study by Antonucci et al (2020) showed the suppression of circulating CD4+ and CD8+ T lymphocytes activation due to infiltration of polymorphonuclear neutrophils (PMNs), which were elevated in NAFLD and NASH patients [ 37 ]. However, a few studies that used liver tissues instead of duodenal tissues displayed contrasting results.…”