Frontiers in immunology · 2026
GM-CSF promotes pro-inflammatory macrophage activation associated with Akt/mTOR signaling during experimental colitis.
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Shen Silan, Chen Kexin, Li Lili, Jiang Mingshan, Jia Yongbin, Bai Xiufeng, Zeng Zhen, Ma Chunxiang, Dang Yuan, Hu Kehan, Chen Yanqiong, Zhang Wenting, Miao Zhiyong, Chen Linlin, Zhang Hu
Аннотация
BACKGROUND: Ulcerative colitis (UC) is an intestinal immune disorder of unknown etiology. Mounting evidence reveals a central role of macrophages in the hemostatic balance of gut immunity, and dysfunctional macrophages are associated with UC pathogenesis. Granulocyte macrophage-colony stimulating factor (GM-CSF) is an essential modulator of macrophages and has recently been recognized as a potential target in many autoimmune disorders. However, the action of GM-CSF in gut inflammation remains unspecified.
METHODS: The significance of GM-CSF in UC and its mechanism of action were investigated. GM-CSF expression was examined in colon biopsy tissues from UC patients and healthy controls. A dextran sodium sulfate (DSS)-induced colitis mouse model was used to evaluate the effect of GM-CSF neutralizing antibody (GM-CSF Ab). Macrophage infiltration, CD4+ T helper (Th) cell responses, macrophage polarization, and glycolysis-related genes were assessed using in vivo and in vitro experiments. The involvement of the Akt/mTOR pathway was also examined.
RESULTS: GM-CSF expression was significantly elevated in colon biopsy tissues from UC patients compared to controls. Administration of GM-CSF Ab to DSS-treated mice attenuated gut inflammation. Furthermore, GM-CSF Ab inhibited the infiltration of macrophages and inflammatory CD4+ Th cells into the intestine of DSS-colitis mice. In vitro experiments showed that GM-CSF induced M1-type polarization of peritoneal macrophages and subsequently augmented the Th17 response. Further experiments indicated that the proinflammatory phenotype of macrophages induced by GM-CSF was related to glycolytic metabolism, which was influenced by the Akt/mTOR pathway.
CONCLUSION: Collectively, this study suggests that GM-CSF is associated with the regulation of glycolytic metabolism involving the Akt/mTOR pathway, and subsequently alters macrophage function to promote intestinal inflammation.
METHODS: The significance of GM-CSF in UC and its mechanism of action were investigated. GM-CSF expression was examined in colon biopsy tissues from UC patients and healthy controls. A dextran sodium sulfate (DSS)-induced colitis mouse model was used to evaluate the effect of GM-CSF neutralizing antibody (GM-CSF Ab). Macrophage infiltration, CD4+ T helper (Th) cell responses, macrophage polarization, and glycolysis-related genes were assessed using in vivo and in vitro experiments. The involvement of the Akt/mTOR pathway was also examined.
RESULTS: GM-CSF expression was significantly elevated in colon biopsy tissues from UC patients compared to controls. Administration of GM-CSF Ab to DSS-treated mice attenuated gut inflammation. Furthermore, GM-CSF Ab inhibited the infiltration of macrophages and inflammatory CD4+ Th cells into the intestine of DSS-colitis mice. In vitro experiments showed that GM-CSF induced M1-type polarization of peritoneal macrophages and subsequently augmented the Th17 response. Further experiments indicated that the proinflammatory phenotype of macrophages induced by GM-CSF was related to glycolytic metabolism, which was influenced by the Akt/mTOR pathway.
CONCLUSION: Collectively, this study suggests that GM-CSF is associated with the regulation of glycolytic metabolism involving the Akt/mTOR pathway, and subsequently alters macrophage function to promote intestinal inflammation.