Evaluation of Tryptophan Metabolism in Chronic Immune Activation

Abstract

AbstractChronic immune activation is encountered in different pathologies including granulomatous and functional bowel diseases, cancer, aging, atherosclerosis, and obesity. Persistence of chronic inflammatory stimuli over time creates a biologic background for immunosenescence and favors neopterin formation with the enhanced tryptophan (Trp) degradation in diseases concomitant with cellular immune activation. Trp degradation leads to the generation of several neuroactive compounds by three distinct pathways.Indoleamine 2,3-dioxygenase (IDO) induction leads to many complex changes within the affected cells resulting in immunosuppression through breakdown of Trp. Thus, neopterin concentrations as well as IDO expression significantly increase in inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease.However, irritable bowel syndrome (IBS) is linked with abnormal serotonin functioning and immune activation. In this case, enteric serotonin (5-HT) signaling may be defective and inactivated by the serotonin-selective reuptake transporter (SERT) in the enterocytes. A positive correlation is evident between IBS severity and kynurenine (Kyn) to Trp ratio which is significantly correlated with the rise of interferon (IFN)-gamma.The dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. IDO-reactive T cells are able to recognize and kill tumor cells as well as IDO-expressing dendritic cells (DCs). IDO activation leads to immunosuppression through breakdown of Trp in the tumor microenvironment and tumor-draining lymph nodes. C-C chemokine receptor type 4 (CCR4)+ forkhead boxp3(Foxp3)+ regulatory T (Treg) cells create a favorable environment for tumor escape from host immune responses. Thus, Foxp3+/IDO+ tumors are associated with more advanced disease.Age-related changes in the immune system are known as immunosenescence. A causal relationship is evident between the Trp metabolism and immune deficiency in elderly. Eventually, the reduced serum Trp concentrations and increased Kyn levels indicate increased chronic low-grade inflammation in elderly. In this case, IDO-induced Trp degradation is associated with increase in neopterin and nitrite levels. The amounts of neopterin produced by activated macrophages correlate with their capacity to release reactive oxygen species (ROS). Melatonin not only improves the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes but also reduces free radical generation. The decline in melatonin production in aged individuals is a primary contributing factor for the development of age-associated neuronal damage.IDO activity also has a significant positive correlation in both sexes with carotid artery intima/media thickness as an early marker of atherosclerosis. Enhanced Trp degradation in patients with coronary heart disease correlates with enhanced neopterin formation. In addition to elevated Kyn to Trp ratio, neopterin concentrations correlate with the abdominal obesity and metabolic syndrome.KeywordsTryptophanKynurenineNeopterinUlcerative colitisCrohn’s diseaseIrritable bowel syndromeImmune escape mechanismsObesityAging