Glycolytic Reprogramming in Silica-Induced Lung Macrophages and Silicosis Reversed by Ac-SDKP Treatment

Abstract

Glycolytic reprogramming is an important metabolic feature in the development of pulmonary fibrosis. However, the specific mechanism of glycolysis in silicosis is still not clear. In this study, silicotic models and silica-induced macrophage were used to elucidate the mechanism of glycolysis induced by silica. Expression levels of the key enzymes in glycolysis and macrophage activation indicators were analyzed by Western blot, qRT-PCR, IHC, and IF analyses, and by using a lactate assay kit. We found that silica promotes the expression of the key glycolysis enzymes HK2, PKM2, LDHA, and macrophage activation factors iNOS, TNF-α, Arg-1, IL-10, and MCP1 in silicotic rats and silica-induced NR8383 macrophages. The enhancement of glycolysis and macrophage activation induced by silica was reduced by Ac-SDKP or siRNA-Ldha treatment. This study suggests that Ac-SDKP treatment can inhibit glycolytic reprogramming in silica-induced lung macrophages and silicosis.

Oxamate Attenuates Glycolysis and ER Stress in Silicotic Mice

“…In addition, it was recently shown that lactate induced the production of reactive oxygen species (ROS) and promoted the expression of UPR genes [ 14 ]. Our previous studies also found that silica induced an increase in extracellular lactate levels in macrophages [ 4 ]. However, it is not clear whether lactate can regulate glycolysis and ER stress in NR8383 macrophages.…”

“…However, some studies have suggested that bone marrow-derived macrophages mainly rely on glycolysis when participating in inflammatory responses, while tissue-resident macrophages mainly rely on oxidative phosphorylation, and glycolysis has been maintained at a low level [ 22 , 23 ]. Our previous study found that tissue-resident macrophages also mainly rely on glycolysis for the production of energy to perform biological functions [ 4 ]. We observed that glycolysis contributed to the regulation of macrophages in silicosis by promoting the activation of M1/M2 macrophages.…”

“…In previous studies, the levels of LDHA and its metabolic product, lactate, were increased in silica-induced rats and mice, indicating that LDHA might be an effective potential therapeutic target for silicosis [ 4 ]. Studies have shown that the LDHA inhibitor gossypol inhibited ionizing radiation and bleomycin-induced pulmonary fibrosis [ 39 , 40 ].…”

“…This metabolic switch from oxidative phosphorylation to glycolytic metabolism provides an energy source for sustaining inflammatory damage [ 3 ]. We previously demonstrated that the levels of key glycolytic enzymes, including hexokinase2 (HK2), pyruvate kinase M2 (PKM2), lactate dehydrogenase A (LDHA), and the lactate concentration were enhanced in silica-induced alveolar macrophage and silicotic models, suggesting that the metabolic switch to glycolysis is an important driving force for the development of silicosis fibrosis [ 4 ].…”

“…However, it is not clear whether lactate can regulate glycolysis and ER stress in NR8383 macrophages. In addition to lactate production, we also found that the expression of LDHA was increased in silica-induced macrophages, and small interfering RNA (siRNA)- Ldha inhibited the activation of these macrophages, giving them an anti-inflammatory role [ 4 ]. However, whether pharmacological inhibition of LDHA plays an anti-fibrotic role by regulating macrophage function remains unclear.…”