RT Journal Article
SR Electronic
T1 The IL-33/ST2 axis affects tumor growth by regulating mitophagy in macrophages and reprogramming their polarization
JF Cancer Biology and Medicine
JO Cancer Biol Med
FD China Anti-Cancer Association
SP 172
OP 183
DO 10.20892/j.issn.2095-3941.2020.0211
VO 18
IS 1
A1 Huadan Xu
A1 Dong Li
A1 Jiaoyan Ma
A1 Yuanxin Zhao
A1 Long Xu
A1 Rui Tian
A1 Yanan Liu
A1 Liankun Sun
A1 Jing Su
YR 2021
UL http://www.cancerbiomed.org/content/18/1/172.abstract
AB Objective: Macrophages are a major component of the tumor microenvironment. M1 macrophages secrete pro-inflammatory factors that inhibit tumor growth and development, whereas tumor-associated macrophages (TAMs) mainly exhibit an M2 phenotype. Our previous studies have shown that the interleukin-33/ST2 (IL-33/ST2) axis is essential for activation of the M1 phenotype. This study investigates the role of the IL-33/ST2 axis in TAMs, its effects on tumor growth, and whether it participates in the mutual conversion between the M1 and M2 phenotypes.Methods: Bone marrow-derived macrophages were extracted from wildtype, ST2 knockout (ST2−/−), and Il33-overexpressing mice and differentiated with IL-4. The mitochondrial and lysosomal number and location, and the expression of related proteins were used to analyze mitophagy. Oxygen consumption rates and glucose and lactate levels were measured to reveal metabolic changes.Results: The IL-33/ST2 axis was demonstrated to play an important role in the metabolic conversion of macrophages from OXPHOS to glycolysis by altering mitophagy levels. The IL-33/ST2 axis promoted enhanced cell oxidative phosphorylation, thereby further increasing M2 polarization gene expression and ultimately promoting tumor growth (P < 0.05) (Figure 4). This metabolic shift was not due to mitochondrial damage, because the mitochondrial membrane potential was not significantly altered by IL-4 stimulation or ST2 knockout; however, it might be associated with the mTOR activity.Conclusions: These results clarify the interaction between the IL-33/ST2 pathway and macrophage polarization, and may pave the way to the development of new cancer immunotherapies targeting the IL-33/ST2 axis.