Elucidating the Role of FoxO3a Signaling in Rescuing Intestinal Inflammation in IL-10-Deficient Murine Hosts

Abstract

The transcription factor FoxO3a plays an essential role in metabolism, cell proliferation, cell differentiation, cell death and stress resistance. Originally identified as a tumor suppressor, FoxO3a was later shown to regulate inflammation by modulating the innate and adaptive immune responses. Recently, genome-wide association studies have identified mutations in the FoxO3a gene that promote the progression of an aggressive course of Crohn’s disease, a form of inflammatory bowel disease in humans. Indeed, mutations in susceptibility genes, such as IL-10, correlate with IBD; however, they may not necessarily impact disease progression implying the existence of compensatory genes. Herein, we unravel the role of FoxO3a in preventing the progression of a spontaneous CrD-like phenotype in an IL-10-deficient mouse model of colitis. Our findings indicate that reduced FoxO3a activity enhances the inflammatory response and leads to a compensatory increase in the expression of IL-10. Deficiency in IL-10 production, in the context of poor FoxO3a signaling, removes all the regulatory brakes and unleashes a pathological inflammatory response in the gut. We show that deficiency in both FoxO3a and IL-10 leads to an abundant presence of death-resistant immune cells in the colon lamina propria, while being constantly replenished by enhanced myelopoiesis in the bone marrow. The myeloid cells exhibit an intrinsic hyperactivation of mTORC1 and other inflammatory signaling pathways resulting in flaming levels of inflammatory mediators. The created pro-inflammatory milieu cannot be attenuated by dysfunctional regulatory T cells despite their abundance in the gut. We also demonstrate that through transcriptional repression of glutaminase (GLS/GLS2), FoxO3a signaling prevents excessive glutaminolysis in activated T cells and downregulates an overt Th17-like immune response. Finally, we show that FoxO3a restricts the abundance of colitogenic microbiota, such that antibiotic administration improves the survival of the FoxO3a⁻ᐟ⁻ Il10⁻ᐟ⁻ mice. In summary, we report that FoxO3a acts as a key checkpoint that restrains the aberrant metabolic activity in myeloid cells and T cells and prevents the accumulation of colitogenic microbiota that contribute altogether to the development of an aggressive form of gut inflammation in Il10⁻ᐟ⁻ hosts. The potent effect of FoxO3a in controlling the severity of gut inflammation, through an intricately antagonistic cooperation with IL -10, brings about a great interest in IBD research and may lead to new therapeutic avenues.