The IL-33/ST2 axis affects tumor growth by regulating mitophagy in macrophages and reprogramming their polarization
Huadan Xu, Dong Li, Jiaoyan Ma, Yuanxin Zhao, Long Xu, Rui Tian, Yanan Liu, Liankun Sun, Jing Su
Abstract
Objective: Macrophages are a major component of the tumor microenvironment. M1 macrophages secrete pro-inflammatory factorsthat inhibit tumor growth and development, whereas tumor-associated macrophages (TAMs) mainly exhibit an M2 phenotype. Ourprevious studies have shown that the interleukin-33/ST2 (IL-33/ST2) axis is essential for activation of the M1 phenotype. This studyinvestigates the role of the IL-33/ST2 axis in TAMs, its effects on tumor growth, and whether it participates in the mutual conversionbetween the M1 and M2 phenotypes. Methods: Bone marrow-derived macrophages were extracted from wildtype, ST2 knockout (ST2−/−), and Il33-overexpressing miceand differentiated with IL-4. The mitochondrial and lysosomal number and location, and the expression of related proteins wereused 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 OXPHOSto glycolysis by altering mitophagy levels. The IL-33/ST2 axis promoted enhanced cell oxidative phosphorylation, thereby furtherincreasing M2 polarization gene expression and ultimately promoting tumor growth (P < 0.05) (Figure 4). This metabolic shift wasnot due to mitochondrial damage, because the mitochondrial membrane potential was not significantly altered by IL-4 stimulationor 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 theway to the development of new cancer immunotherapies targeting the IL-33/ST2 axis.