Glycine Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Regulating NLRP3 Inflammasome and NRF2 Signaling

Abstract

Glycine supplementation has been reported to alleviate lipopolysaccharide (LPS)-induced lung injury in mice. However, the underlying mechanisms responsible for this beneficial effect remain unknown. In the present study, male C57BL/6 mice were treated with aerosolized glycine (1000 mg in 5 mL of 0.9% saline) or vehicle (0.9% saline) once daily for 7 continuous days, and then were exposed to aerosolized LPS (5 mg in 5 mL of 0.9% saline) for 30 min to induce lung injury. Sera and lung tissues were collected 24 h post LPS challenge. Results showed that glycine pretreatment attenuated LPS-induced decreases of mucin at both protein and mRNA levels, reduced LPS-triggered upregulation of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferons, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukins. Further study showed that glycine-reduced LPS challenge resulted in the upregulation of nuclear factor κB (NF-κB), nucleotide binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. In addition, LPS exposure led to the downregulation of NRF2 and downstream targets, which were significantly improved by glycine administration in the lung tissues. Our findings indicated that glycine pretreatment prevented LPS-induced lung injury by regulating both NLRP3 inflammasome and NRF2 signaling.

The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging

“…Concurrently, exogenous glycine increased Nrf2 signaling, activating cellular oxidative stress responses such as HO-1. Together, exogenous glycine attenuates IL-1β production by decreasing the expression of NLRP3 inflammasome components [114]. Collectively, these studies demonstrate that the diverse pool of cellular amino acids has the ability to positively and negatively regulate the NLRP3 inflammasome ( Figure 2).…”

“…Lastly, the amino acid glycine was shown to inhibit NLRP3 inflammasome activation in a model of lung injury [114]. Mechanistically, exogenous glycine was found to attenuate LPS induced NF-κB activation, without altering protein abundance of the upstream proteins TLR4 or MyD88.…”

rhKGF-2 Attenuates Smoke Inhalation Lung Injury of Rats via Activating PI3K/Akt/Nrf2 and Repressing FoxO1-NLRP3 Inflammasome

“…NLRP3 inflammasome is activated in diversified lung injuries. For instance, Zhang et al, 2020; showed that Glycine prevents LPSinduced lung injury by inactivating NLRP3 and enhancing Nrf2 (Sun et al, 2018). Other scholars have found that Diosmetin attenuates LPS-induced acute lung injury by activating Nrf2 and inhibiting NLRP3 (Liu et al, 2018).…”

Role of NLRP3 Inflammasome Activation in Obesity-Mediated Metabolic Disorders

“…An increase in glutamate during ischemic conditions of glucose deprivation and hypoxia induces ER stress, Ca 2+ influx, and TXNIP expression, resulting in NLRP3 inflammasome activation [ 102 ]. The amino acid glycine was found to attenuate IL-1β production by decreasing the expression of NLRP3 inflammasome components [ 103 ]. The best-characterized stimuli of the NLRP3 inflammasome is ATP (nucleotide-containing DAMP), which regulates it in a manner beyond the initial upregulation of IL-1β by NF-κB [ 104 ].…”