# Indoleamine 2,3-dioxygenase-regulated macrophages metabolic reprogramming rescues tacrolimus-induced nephrotoxicity

## TL;DR

The study shows how restoring NAD+ through kynurenine or PPARα activation can reverse kidney damage caused by tacrolimus.

## Contribution

The novel finding is that IDO1-regulated macrophage metabolism and NAD+ synthesis are critical in tacrolimus-induced nephrotoxicity.

## Key findings

- Tacrolimus suppresses IDO1 activity, blocking tryptophan to kynurenine conversion and impairing NAD+ synthesis.
- NAD+ deficiency promotes M1 macrophage polarization and worsens kidney injury.
- Restoring NAD+ via kynurenine or PPARα activation reverses metabolic imbalance and kidney damage.

## Abstract

Macrophage metabolic reprogramming toward the M1 phenotype is a key pathological feature of kidney injury. Recent studies have increasingly highlighted the importance of de novo NAD+ synthesis in the development of renal damage. In this study, we found that tacrolimus (TAC) suppressed the activity of indoleamine-2,3-dioxygenase 1 (IDO1), thereby blocking the conversion of tryptophan (Trp) to kynurenine (KYN), impairing de novo NAD+ synthesis. NAD+ deficiency enhances glycolysis, causes accumulation of medium-to long-chain fatty acids and acylcarnitines, indicating impaired fatty acid β-oxidation, thereby promoting M1 polarization and exacerbating renal injury. Further investigations revealed that restoring NAD+ levels via exogenous KYN supplementation or directly activating peroxisome proliferator-activated receptor alpha (PPARα) to enhance fatty acid oxidation effectively reversed this metabolic imbalance and alleviated TAC-induced kidney injury.

Flowchart illustrating the TAC-IDO1 pathway inhibiting metabolic products from tryptophan (TRP) metabolism, leading to altered macrophage metabolic reprogramming, shifts toward M1 macrophages, decreased M2 macrophages, affecting PPAR-alpha activation, and resulting in kidney injury; KYN supplementation counteracts this process.