Lack of mTORC2 signaling in CD11c+ myeloid cells inhibits their migration and ameliorates experimental colitis

Ignacio, A.; Cipelli, M.; Takiishi, T.; Aguiar, C. F.; Terra, F. F.; Ghirotto, B.; Silva, E. M.; Castoldi, A.; Magalhaes, Y. T.; Antonio, T.; Hiyane, M. I.; Andrade-Oliveira, V.; Forti, F. L.; Camara, N. O. S.

doi:10.1101/2023.04.26.537895

bioRxiv · 10.1101/2023.04.26.537895

Lack of mTORC2 signaling in CD11c+ myeloid cells inhibits their migration and ameliorates experimental colitis

Ignacio, A.·Cipelli, M.·Takiishi, T.·Aguiar, C. F.·Terra, F. F.·Ghirotto, B.·Silva, E. M.·Castoldi, A.·Magalhaes, Y. T.·Antonio, T.·Hiyane, M. I.·Andrade-Oliveira, V.·Forti, F. L.·Camara, N. O. S.

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Abstract

Mammalian target of rapamycin (mTOR) pathway plays a key role in determining immune cells function through modulation of their metabolic status. By specific deletion of Rictor in tissue-resident CD11c+ myeloid cells (CD11cRic{Delta}/{Delta}), this study investigated the role of mTOR complex 2 (mTORC2) signaling in dendritic cells (DCs) function in mice. We showed that upon DSS-induced colitis, lack of mTORC2 signaling CD11c+ cells diminish colonic inflammation, abrogates dendritic cell (DC) migration to the mesenteric lymph nodes (MLN), thereby diminishing the infiltration of T helper (Th) 17 cells in the lamina propria (LP). These findings corroborate with abrogation of cytoskeleton organization and decreased activation of Rac1 and Cdc42 GTPases observed in CD11c+-mTORC2-deficient cells. Meta-analysis on colonic samples from ulcerative colitis (UC) patients revealed increased gene expression of pro-inflammatory cytokines which coincided with augmented expression of mTOR pathway, positive correlation between the DC marker ITGAX, and IL-6, the expression of RICTOR, and CDC42. Together, this work proposes that targeting mTORC2 on DCs offers a key to hamper inflammatory responses and this way, ameliorates the progression and severity of intestinal inflammatory diseases.

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Ignacio, A., Cipelli, M., Takiishi, T., Aguiar, C. F., Terra, F. F., Ghirotto, B., Silva, E. M., Castoldi, A., Magalhaes, Y. T., Antonio, T., Hiyane, M. I., Andrade-Oliveira, V., Forti, F. L., Camara, N. O. S.. 2023-04-28. Lack of mTORC2 signaling in CD11c+ myeloid cells inhibits their migration and ameliorates experimental colitis. https://doi.org/10.1101/2023.04.26.537895

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