Anti-inflammatory Function of NMN in Macrophages via IDO1/Kynurenine/AhR Axis

Anti-inflammatory Function of NMN in Macrophages via IDO1/Kynurenine/AhR Axis


1. Introduction

Nicotinamide mononucleotide (NMN) supplementation has been suggested to hamper the inflammatory responses via restoring NAD+ level and downregulating the expression of Cyclooxygenase-2 (COX-2). Strikingly, both Aryl hydrocarbon receptor (AhR) and Indoleamine 2,3-Dioxygenase 1 (IDO1), two key enzymes for kynurenine production, can mediate the anti-inflammatory function of NMN in RAW 264.7 macrophages.

2. The alleviated inflammatory response in the presence of NMN supplementation

For deciphering the impact of NMN in vivo, mice are subjected to daily intraperitoneal (i.p.) injection of NMN (500 mg/kg) for consecutive 6 days, followed by i.p. injection of lipopolysaccharides (LPS) (5 mg/kg) or alum (700 μg) on day 7. It is discovered that NMN supplementation suppresses LPS- or alum-induced inflammation in mice, as manifested by the downregulation of proinflammatory cytokines (IL-6 and IL-1β) and proinflammatory enzyme (COX-2). 

3. The necessity of AhR for NMN-mediated inhibition of inflammatory response in macrophages

AhR, a ligand-activated transcription factor, can mediate the anti-inflammatory function of NMN upon LPS treatment in RAW264.7 cells. Specifically, NMN reduces the expression of COX-2 in cells in bearing AHR. On the contrary. AhR inhibitor (CH223191) deprives the downregulation of IL-6, IL-1β and COX-2 caused by NMN treatment. Likewise, NMN treatment fails to reduce the expression levels of IL-6, IL-1β, and COX-2 in AhR knockout cells.

4. The importance of IDO1/kynurenine/AhR axis in the anti-inflammation function of NMN

IDO1 is the rate-limiting enzyme in tryptophan catabolism to produce kynurenine, a metabolic intermediate in NAD+ de novo synthesis pathway. Kynurenine can promote the translocation of AhR from the cytoplasm to nucleus, thereby exerting an anti-inflammatory effect. NMN inhibits LPS-induced inflammation in a IDO1-kynurenine dependent manner in macrophages.

5. Conclusion

NMN supplementation mitigates COX-2-associated inflammatory responses by activating lDO-kynurenine-AhR pathway, providing new insights into NAD* regulation in macrophage activation.


Liu J, Hou W, Zong Z, et al. Supplementation of nicotinamide mononucleotide diminishes COX-2 associated inflammatory responses in macrophages by activating kynurenine/AhR signaling. Free Radic Biol Med. Published online February 8, 2024. doi:10.1016/j.freeradbiomed.2024.01.046


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Unveiling the Modulation of NMN Supplementation on Mitochondrial Homeostasis

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