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

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.

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). 

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.

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.

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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