Abstract
Macrophage activation is an important process in controlling infection, but persistent macrophage activation leads to chronic inflammation and diseases, such as tumor progression, insulin resistance and atherosclerosis. Characterizing metabolic signatures of macrophage activation is important for developing new approaches for macrophage inactivation. Herein, we performed metabolomic analysis on lipopolysaccharide (LPS)-activated macrophages and identified the associated changes in metabolites. Notably, the cellular Nicotinamide adenine dinucleotide+ levels were decreased while NADPH was increased, proposing that NAD+ restoration can inhibit macrophage activation. Indeed, supplementation of nicotinamide mononucleotide (NMN) increased cellular NAD+ levels and decreased cytokine productions in LPS-activated cells. Quantitative proteomics identified that nicotinamide mononucleotide downregulated the expressions of LPS-responsive proteins, in which cyclooxygenase-2 (COX-2) expression was significantly decreased in NMN-treated cells. Consequently, the cellular levels of prostaglandin E2 (PGE2) was also decreased, indicating that NMN inactivated macrophages via COX-2-PGE2 pathway, which was validated in activated THP-1 cells and mouse peritoneal macrophages. In conclusion, the present study identified the metabolic characteristics of activated macrophages and revealed that NMN replenishment is an efficient approach for controlling macrophage activation.
Highlights
Inflammation is an adaptive process when the human body constantly exposes to harmful stimuli (Medzhitov, 2008)
We found the levels of citrulline and oxoglutaric acid associated with CitrullineNitric Oxide Cycle were increased in LPS-treated RAW264.7 cells whereas levels of 3-hydroxyoctanoyl carnitine, Linoleyl carnitine, Heptadecanoyl carnitine and Propionylcarnitine related to carnitine metabolism were decreased
We revealed the metabolic and proteomic signatures of macrophage activation and demonstrated that nicotinamide mononucleotide (NMN) supplementation efficiently alleviated LPS-induced inflammation
Summary
Inflammation is an adaptive process when the human body constantly exposes to harmful stimuli (Medzhitov, 2008). Macrophages play an important role in the initiation, maintenance, and resolution of inflammation through production of various cytokines and growth factors (Kasahara and Matsushima, 2001). Activated M1 macrophages promotes inflammation by secreting cytokines, such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), nitric oxide (NO) and prostaglandins (PGE2) (Fujiwara and Kobayashi, 2005). PGE2 that mediates inflammatory response is synthesized from arachidonic acid by cyclooxygenases (COX-1 and COX-2) (Ricciotti and FitzGerald, 2011). COX-1 and COX-2 are the targets of anti-inflammation, and are inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) (Kerola et al, 2009; Tóth et al, 2013). Finding new anti-inflammatory molecules is important for inflammation management
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