Endotoxin-Induced Tryptophan Degradation along the Kynurenine Pathway: The Role of Indolamine 2,3-Dioxygenase and Aryl Hydrocarbon Receptor-Mediated Immunosuppressive Effects in Endotoxin Tolerance and Cancer and Its Implications for Immunoparalysis

Abstract

The degradation of tryptophan (TRP) along the kynurenine pathway plays a crucial role as a neuro- and immunomodulatory mechanism in response to inflammatory stimuli, such as lipopolysaccharides (LPS). In endotoxemia or sepsis, an enhanced activation of the rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO) is associated with a higher mortality risk. It is assumed that IDO induced immunosuppressive effects provoke the development of a protracted compensatory hypoinflammatory phase up to a complete paralysis of the immune system, which is characterized by an endotoxin tolerance. However, the role of IDO activation in the development of life-threatening immunoparalysis is still poorly understood. Recent reports described the impact of inflammatory IDO activation and aryl hydrocarbon receptor- (AhR-) mediated pathways on the development of LPS tolerance and immune escape of cancer cells. These immunosuppressive mechanisms offer new insights for a better understanding of the development of cellular dysfunctions in immunoparalysis. This review provides a comprehensive update of significant biological functions of TRP metabolites along the kynurenine pathway and the complex regulation of LPS-induced IDO activation. In addition, the review focuses on the role of IDO-AhR-mediated immunosuppressive pathways in endotoxin tolerance and carcinogenesis revealing the significance of enhanced IDO activity for the establishment of life-threatening immunoparalysis in sepsis.

EWS‐FLI1 impairs aryl hydrocarbon receptor activation by blocking tryptophan breakdown via the kynurenine pathway

“…TRP degradation in cancers has mostly been attributed to the activity of IDO1 in cancer cells and tumor‐draining lymph nodes . Alternatively, in the absence of IDO1, TDO2 can overtake the constitutive TRP breakdown and KYN production in some human cancers and specialized myeloid cells .…”

The Immunomodulator 1-Methyltryptophan Drives Tryptophan Catabolism Toward the Kynurenic Acid Branch

“…1-methyltryptophan (1-MT) is a TRP analog described first in 1991 (1) as a potential competitive inhibitor of the enzyme indoleamine 2,3-dioxygenase (IDO1). IDO1 is one rate-limiting enzyme of the kynurenine pathway (KP) (Figure 1), which plays a crucial role in the regulation of the immune response, notably as a counter-regulatory mechanism in the context of inflammation (2,3). In (2,3)].…”

“…IDO1 is one rate-limiting enzyme of the kynurenine pathway (KP) (Figure 1), which plays a crucial role in the regulation of the immune response, notably as a counter-regulatory mechanism in the context of inflammation (2,3). In (2,3)]. Black arrows mark enzymatic reactions and dashed arrows include more than one catalytic reaction step.…”

Antioxidant Properties of Kynurenines: Density Functional Theory Calculations

“…The implication of KP in a variety of physiological and pathophysiological processes, including anti-microbial and anti-tumor defense, neuropathology, immunoregulation, and antioxidant activity, has been ever drawing attention to biochemical properties of kynurenines [1]. Kynurenines are considered to be involved in ageing and numerous neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), etc.…”