Deficiency in IL-33/ST2 Axis Reshapes Mitochondrial Metabolism in Lipopolysaccharide-Stimulated Macrophages

Abstract

The polarization and function of macrophages play essential roles in controlling immune responses. Interleukin (IL)-33 is a member of the IL-1 family that has been shown to influence macrophage activation and polarization, but the underlying mechanisms are not fully understood. Mitochondrial metabolism has been reported to be a central player in shaping macrophage polarization; previous studies have shown that both aerobic glycolysis and oxidative phosphorylation uniquely regulate the functions of M1 and M2 macrophages. Whether IL-33 polarizes macrophages by reshaping mitochondrial metabolism requires further investigation. In this work, we examined the mitochondrial metabolism of bone marrow-derived macrophages (BMDMs) from either wild type (WT), Il33-overexpressing, or IL-33 receptor knockout (St2−/−) mice challenged with lipopolysaccharide (LPS). We found that after LPS stimulation, compared with WT BMDMs, St2−/− BMDMs had reduced cytokine production and increased numbers and activity of mitochondria via the metabolism regulator peroxisome proliferator-activated receptor-C coactivator-1 α (PGC1α). This was demonstrated by increased mitochondrial DNA copy number, mitochondria counts, mitochondria fission- and fusion-related gene expression, oxygen consumption rates, and ATP production, and decreased glucose uptake, lactate production, and extracellular acidification rates. For Il33-overexpressing BMDMs, the metabolic reprogramming upon LPS stimulation was similar to WT BMDMs, and was accompanied by increased M1 macrophage activity. Our findings suggested that the pleiotropic IL-33/ST2 pathway may influence the polarization and function of macrophages by regulating mitochondrial metabolism.

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

“…Although the molecular mechanisms regulating macrophages polarization are poorly understood, these cells have been reported to be metabolically reprogrammed during polarization [143]. So the PGC-1α-dependent regulation of mitochondrial function would play an essential role here [144]. Intriguing accumulated evidence suggests a critical role of ROS in regulating macrophage polarization [145], but the specific contribution of ROS levels controlled by PGC-1α during this process is an exciting question yet to be addressed.…”

The IL-33/ST2 axis affects tumor growth by regulating mitophagy in macrophages and reprogramming their polarization

“…Primary bone-marrow derived macrophages (BMDMs) were generated and cultured as previously described 27 . IL-4 was purchased from BioLegend (San Diego CA, US).…”

“…Total RNA was extracted from BMDMs as previously described 27 . Genomic DNA digestion and reverse transcription were performed according to the manufacturer’s instructions.…”

“…Our previous studies have shown that mitochondrial metabolism is a core player in the macrophage polarization process. The IL-33/ST2 axis plays an important role in the metabolic reprogramming of M1 macrophages, through regulating the level of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which is associated with mitochondrial biosynthesis 27 . However, the role of IL-33 in regulating M2 macrophage polarization remains elusive 20 , 25 , 28 .…”

Inhibition of pyruvate dehydrogenase kinase‑1 by dicoumarol enhances the sensitivity of hepatocellular carcinoma cells to oxaliplatin via metabolic reprogramming

“…Male BALB/c-nu mice aged 6 weeks old and weighing approximately 15 g each were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. They were kept at temperature (22-24°C) with a stable humidity (55±15%) with free access to food/water in a 12 h/12 h light/dark cycle and housed in specific pathogen-free conditions at Jilin University ( 19 ). A total of 5×10 6 SNU-449 cells were subcutaneously injected into the backs of the mice.…”