Huadan Xu1, Dong Li2,3, Jiaoyan Ma1, Yuanxin Zhao1, Long Xu1, Rui Tian1, Yanan Liu1, Liankun Sun1, Jing Su1. 1. Key Laboratory of Pathobiology, Ministry of Education, Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun 130000, China. 2. Department of Hepatology, The First Hospital of Jilin University, Changchun 130000, China. 3. Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun 130000, China.
Abstract
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. Copyright:
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. Copyright:
Authors: Jose C Alves-Filho; Fabiane Sônego; Fabricio O Souto; Andressa Freitas; Waldiceu A Verri; Maria Auxiliadora-Martins; Anibal Basile-Filho; Andrew N McKenzie; Damo Xu; Fernando Q Cunha; Foo Y Liew Journal: Nat Med Date: 2010-05-16 Impact factor: 53.440