Nicotinamide mononucleotide alleviates endotoxin-induced acute lung injury by modulating macrophage polarization via the SIRT1/NF-κB pathway

Abstract

Context

Sepsis-induced acute lung injury (ALI) is a severe condition with limited effective therapeutics; nicotinamide mononucleotide (NMN) has been reported to exert anti-inflammatory activities.

Objective

This study explores the potential mechanisms by which NMN ameliorates sepsis-induced ALI in vivo and in vitro.

Materials and methods

Cultured MH-S cells and a murine model were used to evaluate the effect of NMN on sepsis-induced ALI. MH-S cells were stimulated with LPS (1 μg/mL) and NMN (500 μM) for 12 h grouping as control, LPS, and LPS + NMN. Cell viability, apoptotic status, and M1/2 macrophage-related markers were detected. The mice were pretreated intraperitoneally with NMN (500 mg/kg) and/or EX-527 (5 mg/kg) 1 h before LPS injection and randomized into 7 groups (n = 8): control, LPS, LPS + NMN, NMN, LPS + NMN + EX-527 (a SIRT1 inhibitor), LPS + EX-527, and EX-527. After 12 h, lung histopathology, W/D ratio, MPO activity, NAD⁺ and ATP levels, M1/2 macrophage-related markers, and expression of the SIRT1/NF-κB pathway were detected.

Results

In MH-S cells, NMN significantly decreased the apoptotic rate from 12.25% to 5.74%. In septic mice, NMN improved the typical pathologic findings in lungs and reduced W/D ratio and MPO activity, but increased NAD⁺ and ATP levels. Additionally, NMN suppressed M1 but promoted M2 polarization, and upregulated the expression of SIRT1, with inhibition of NF-κB-p65 acetylation and phosphorylation. Furthermore, inhibition of SIRT1 reversed the effects of NMN-induced M2 macrophage polarization.

Conclusions

NMN protects against sepsis-induced ALI by promoting M2 macrophage polarization via the SIRT1/NF-κB pathway, it might be an effective strategy for preventing or treating sepsis-induced ALI.

Keywords:

• NMN
• septic lung injury
• NAD⁺

Authors’ contributions

SMH and JBY conceived and designed the experiments, the experiments in MH-S cells were performed by XHJ, XYW and SHD, and experiments in animal models were performed by SMH, JY, and SAD. Experimental analysis was performed by YW, JS, YZ and LRG; the first draft of the manuscript was written by SMH and all authors commented on previous versions of the manuscript; all authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (grant No.82074153 and 81900041); the Natural Science Foundation of Tianjin (grant No. 20JCYBJC00540, 20JCZDJC00480); the Science and Technology Plan Project of Tianjin (grant No. 21JCYBJC01240).