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

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Ignacio, Aline ; Cipelli, Marcella ; Takiishi, Tatiane ; Aguiar, Cristhiane Favero ; Fernandes Terra, Fernanda ; Ghirotto, Bruno ; Silva, Eloisa Martins ; Castoldi, Angela ; Magalhaes, Yuli Thamires ; Antonio, Tiago ; Padovani, Barbara Nunes ; Ioshie Hiyane, Meire ; Andrade-Oliveira, Vinicius ; Forti, Fabio Luis ; Camara, Niels Olsen Saraiva

• Document type: Journal article
• Source: Journal of Leukocyte Biology; v. 116, n. 4, p. 14-pg., 2024-04-23.

Abstract

The 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 CD11c(+) myeloid cells (referred to here as CD11cRic Delta/Delta), we investigated the role of mTOR complex 2 (mTORC2) signaling in dendritic cells (DCs) function in mice. We showed that upon dextran sulfate sodium-induced colitis, the lack of mTORC2 signaling CD11c(+) cells diminishes the colitis score and abrogates DC migration to the mesenteric lymph nodes, thereby diminishing the infiltration of T helper 17 cells in the lamina propria and subsequent inflammation. These findings corroborate with the abrogation of cytoskeleton organization and the decreased activation of Rac1 and Cdc42 GTPases observed in CD11c(+)-mTORC2-deficient cells. Meta-analysis on colonic samples from ulcerative colitis patients revealed increased gene expression of proinflammatory cytokines, which coincided with augmented expression of the mTOR pathway, a positive correlation between the DC marker ITGAX and interleukin-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. (AU)

• FAPESP's process: 17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants