Ammonia Drives Dendritic Cells into Dysfunction

Abstract

Ammonia levels are often elevated in patients with cirrhosis or tumors. Patients with these diseases are immunocompromised. In this study, we investigated the effects of ammonia on a member of the immune cell family, the dendritic cells (DCs). Our results demonstrated that ammonia diminished cell count, phagocytosis, and lymphocyte stimulation of DCs. Ammonia also induced DC swelling, excessive reactive oxygen species production, and mitochondrial damage, which may constitute the underlying mechanism of ammonia-induced DC dysfunction. In ammonium chloride (NH4Cl)–loaded mice, DCs exhibited lowered phagocytosis and a weakened immune response to the chicken OVA vaccine. DCs from patients with cirrhosis or ammonia-treated healthy human blood both exhibited diminished phagocytosis. Moreover, tumor cell conditioned medium drove DCs into dysfunction, which could be reversed by ammonia elimination. In a murine colon carcinoma model, we found that ammonia could regulate tumor growth involving DCs and their related immune response. These findings reveal that ammonia could drive DCs into dysfunction, which contributes to the immunocompromised state of patients with cirrhosis or tumors.

Ammonia promotes endothelial cell survival via the heme oxygenase-1-mediated release of carbon monoxide

“…Incubation of HUVECs with ammonia evokes a marked increase in ROS production. This finding mirrors previous work in other cells including astrocytes, neurons, dendritic cells, and epithelial cells [9,12,27,57]. Significantly, the antioxidant NAC blocks the ammonia-mediated generation of ROS, the induction of HO-1, and the activation of Nrf2.…”

Ammonium ions improve the survival of glutamine-starved hybridoma cells

“…On the other hand, it is generally recognized that another product of glutaminolysis, the ammonium ion (NH 4 + ), is detrimental to cells. Its effects vary according to cell types, from functional disruption [ 21 , 22 ] to growth inhibition [ 23 , 24 ] and death [ 25 – 28 ]. However, ammonium ions have also been shown to prevent the induction of apoptosis [ 29 , 30 ], raising the possibility that the perturbations in ammonium ion metabolism occurring under situations of Gln starvation could contribute to the initiation of death pathways.…”

The Measurement of Ammonia in Human Breath and its Potential in Clinical Diagnostics

“…Noiret et al (2014) have developed a mathematical model of portosystemic shunting in cirrhosis to monitor hyperammonaemia to be used in conjunction with other monitoring techniques such as ammonia levels (Noiret et al, 2014). Ammonia has also been shown to drive dendritic immune cells into dysfunction which contributes to the immunocompromised state of cirrhosis (Auffermann-Gratzinger et al, 2001) and tumour patients (Luo et al, 2014).…”

“…In healthy individuals, ammonia levels in the portal vein are higher than in the hepatic vein because ammonia is removed by the liver. Patients with liver disease may develop portal collateral veins (varices) that bypass the liver and divert portal blood with high ammonia levels to systemic circulation (figure 3) (Frontera, 2014;Imran et al, 2012;Luo et al, 2014). Noiret et al (2014) have developed a mathematical model of portosystemic shunting in cirrhosis to monitor hyperammonaemia to be used in conjunction with other monitoring techniques such as ammonia levels (Noiret et al, 2014).…”