Indoleamine 2,3 Dioxygenase 1—The Potential Link between the Innate Immunity and the Ischemia-Reperfusion-Induced Acute Kidney Injury?

Abstract

Ischemia-reperfusion injury (IRI) is of the most common causes of acute kidney injury (AKI); nevertheless, the mechanisms responsible for both early kidney injury and the reparative phase are not fully recognised. The inflammatory response following ischemia is characterised by the crosstalk between cells belonging to the innate immune system—dendritic cells (DCs), macrophages, neutrophils, natural killer (NK) cells, and renal tubular epithelial cells (RTECs). A tough inflammatory response can damage the renal tissue; it may also have a protective effect leading to the repair after IRI. Indoleamine 2,3 dioxygenase 1 (IDO1), the principal enzyme of the kynurenine pathway (KP), has a broad spectrum of immunological activity from stimulation to immunosuppressive activity in inflamed areas. IDO1 expression occurs in cells of the innate immunity and RTECs during IRI, resulting in local tryptophan (TRP) depletion and generation of kynurenines, and both of these mechanisms contribute to the immunosuppressive effect. Nonetheless, it is unknown if the above mechanism can play a harmful or preventive role in IRI-induced AKI. Despite the scarcity of literature in this field, the current review attempts to present a possible role of IDO1 activation in the regulation of the innate immune system in IRI-induced AKI.

Metabolic Modulation of Cellular Function

“…The key enzyme kynurenine-3-monooxygenase (KMO), responsible for converting KYN to 3-HK in human kidneys, is located on the outer membrane of PTECs (Zheng et al, 2019). After AKI, the activity of the IDO enzyme increases in renal TECs leading to an increase in KP decomposition (Krupa et al, 2022). Studies have shown that the expression of KMO in renal TECs decreases in a dose-dependent manner after treatment with cisplatin, resulting in an increase in KYN entering the KYNA and NAD branch (Tan et al, 2021).…”

“…Following AKI onset, the levels of amino acids in renal tubular cells significantly decrease . Up-regulation of IDO enzyme-induced tryptophan depletion can increase the autophagic flux in human renal TECs by activating eukaryotic initiation factor 2 (eIF2α) kinase general control non-derepressible 2 (GCN2) (Fougeray et al, 2012;Krupa et al, 2022). Chaudhary et al (2015) found that increasing renal IDO1 activity or inducing autophagy with GCN2 agonists can protect mice from renal inflammatory injury.…”

Energy metabolic reprogramming regulates programmed cell death of renal tubular epithelial cells and might serve as a new therapeutic target for acute kidney injury

“…The key enzyme kynurenine-3-monooxygenase (KMO), responsible for converting KYN to 3-HK in human kidneys, is located on the outer membrane of PTECs ( Zheng et al, 2019 ). After AKI, the activity of the IDO enzyme increases in renal TECs leading to an increase in KP decomposition ( Krupa et al, 2022 ). Studies have shown that the expression of KMO in renal TECs decreases in a dose-dependent manner after treatment with cisplatin, resulting in an increase in KYN entering the KYNA and NAD branch ( Tan et al, 2021 ).…”

“…IDO upregulation leads to the depletion of tryptophan (TRP), which can activate the general control non-derepressible 2 kinases (GCN2K) pathway and inhibit the mammalian target of rapamycin (mTOR) signaling, thereby promoting renal TEC’s apoptosis. Increased IDO activity can also regulate cysteine aspartic protease-8 activation and TECs apoptosis via the Fas/Fas ligand (FasL) -dependent mechanism ( Krupa et al, 2022 ). The metabolism of polyamines produces ROS and reactive aldehyde, which are important inducing factors for DNA damage, mitochondrial damage, endoplasmic reticulum stress/unfolded protein response, and can trigger TEC’s apoptosis and AKI renal tubular injury ( Zahedi et al, 2019 ).…”

Indoleamine 2, 3-dioxygenase 1 inhibitory compounds from natural sources

“…L-Trp consumption and Kyn production are key to immune system regulation under both physiological and disease conditions (Maddison and Giorgini, 2015;Barreto et al, 2018;Odunsi et al, 2022). Recent studies have continued to highlight the importance of L-Trp metabolism in immune regulation, neuronal function, and ageing (Sorgdrager et al, 2019;Platten et al, 2021;Krupa et al, 2022;Merlo et al, 2022;Ouyang et al, 2022;Salminen, 2022).…”