GM-CSF promotes pro-inflammatory macrophage activation associated with Akt/mTOR signaling during experimental colitis.

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.