Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

Abstract

Quinolinate (Quin) is a classic example of a biochemical double-edged sword, acting as both essential metabolite and potent neurotoxin. Quin is an important metabolite in the kynurenine pathway of tryptophan catabolism leading to the de novo synthesis of nicotinamide adenine dinucleotide (NAD + ). As a precursor for NAD + , Quin can direct a portion of tryptophan catabolism toward replenishing cellular NAD + levels in response to inflammation and infection. Intracellular Quin levels increase dramatically in response to immune stimulation [e.g., lipopolysaccharide (LPS) or pokeweed mitogen (PWM)] in macrophages, microglia, dendritic cells, and other cells of the immune system. NAD + serves numerous functions including energy production, the poly ADP ribose polymerization (PARP) reaction involved in DNA repair, and the activity of various enzymes such as the NAD + -dependent deacetylases known as sirtuins. We used highly specific antibodies to protein-coupled Quin to delineate cells that accumulate Quin as a key aspect of the response to immune stimulation and infection. Here, we describe Quin staining in the brain, spleen, and liver after LPS administration to the brain or systemic PWM administration. Quin expression was strong in immune cells in the periphery after both treatments, whereas very limited Quin expression was observed in the brain even after direct LPS injection. Immunoreactive cells exhibited diverse morphology ranging from foam cells to cells with membrane extensions related to cell motility. We also examined protein expression changes in the spleen after kynurenine administration. Acute (8 h) and prolonged (48 h) kynurenine administration led to significant changes in protein expression in the spleen, including multiple changes involved with cytoskeletal rearrangements associated with cell motility. Kynurenine administration resulted in several expression level changes in proteins associated with heat shock protein 90 (HSP90), a chaperone for the aryl-hydrocarbon receptor (AHR), which is the primary kynurenine Moffett et al.Quinolinate as Kynurenine Marker and NAD + Source metabolite receptor. We propose that cells with high levels of Quin are those that are currently releasing kynurenine pathway metabolites as well as accumulating Quin for sustained NAD + synthesis from tryptophan. Further, we propose that the kynurenine pathway may be linked to the regulation of cell motility in immune and cancer cells.

Immunotherapy of COVID-19 with poly (ADP-ribose) polymerase inhibitors: starting with nicotinamide

“…The role of NAD + in the maintenance of homoeostasis and integrity of the immune system is an undisputed fact [ 95 ]. In infection, the increased demand for NAD + is necessitated by a variety of changes, including enhanced activities of PARP 1, SIRT 1, NAD + hydrolase and cell surface ADP ribosyl transferases [ 95 , 96 ]. In COVID-19 infection, it is more likely that efforts at replenishing NAD + levels will be more important than PARP 1 inhibition per se , at least under conditions involving moderate activation of PARP 1.…”

“…NAD + synthesis is achieved mainly from dietary Trp in the de novo biosynthetic pathway, rather than via the Preiss-Handler ‘salvage’ pathway from NAM or nicotinic acid, with quinolinic acid playing an important role [ 26 , 95 , 96 ]. A comparison of the relative contributions of these three NAD + precursors and also the NAM derivatives NAM riboside (NAMR) and reduced NAMR (NAMRH) to increased NAD + availability may help refine the choice of the most appropriate precursor for COVID-19 therapy.…”

Microglia: Agents of the CNS Pro-Inflammatory Response

“…Tryptophan plays a key role in modulating immune function through its catabolism by the enzyme indoleamine-2,3-dioxygenase (IDO) into kynurenine and its downstream pathways [338]. An inflammatory response is known to stimulate IDO expression and, thus, catabolism of tryptophan to kynurenine [298].…”

“…An inflammatory response is known to stimulate IDO expression and, thus, catabolism of tryptophan to kynurenine [298]. Of importance is the plausible immunomodulatory and immunosuppressive effects that these metabolic products display [338]. The generation of kynurenine and its possible metabolic products quinolinic acid, 3-hydroxykynurenine and kynurenic acid act by different mechanisms in astrocytes and microglia (reviewed in [339]).…”

Targeting Dietary and Microbial Tryptophan-Indole Metabolism as Therapeutic Approaches to Colon Cancer

“…We then discuss the alterations that occur in these pathways during colon cancer. Next, we introduce the significance of the microbial degradation of Trp in healthy conditions, along with the repercussions of microbial alterations common to most of these disease states, Trp is shunted into the Kyn pathway, especially in the extrahepatic tissue (mostly immune cells), while the hepatic pathway activity is reduced [9], [25], [35]. This shunting of Trp into Kyn pathway, reduces Trp availability for other pathways especially serotonin and indolic pathways; the two pathways which have shown to be beneficial for host health in the presence of Trp [34], [36], [37].…”