Loss of Foxo3a—IL-10 antagonism promotes terminal myelopoiesis via Dgat2-mediated upregulation of lipid droplet accumulation 2253907

Abstract Introduction Haematopoietic Stem Cells (HSCs) have the potential to develop into all the blood and immune cells in the body through haematopoiesis. This stepwise differentiation of lineage-committed HSCs is primarily governed by a range of transcription factors and epigenetic modulators. However, inflammatory signals from infections and acute or chronic conditions can impact the functional and differentiation capacity of HSCs, activating the first responders and driving HSC differentiation towards myeloid cell type, triggering a state of emergency myelopoiesis, thereby disrupting homeostasis. The transcription factor Foxo3a is an important modulator of cellular processes such as cell cycle, apoptosis, and DNA repair. While Foxo3a acts as a tumor suppressor, it has also been implicated in attenuating inflammatory responses. We have previously reported that Foxo3a prevents the development of spontaneous and fulminant inflammatory response in the gut of Il10-deficient mice. Since myeloid cells, generated in Bone Marrow (BM), are the primary mediators of potent inflammatory response, we hypothesized that Foxo3a may inhibit the key cell signaling mechanisms in the BM compartment to restrict the escalation of inflammatory response in Il10-deficient mice. Methods BM cells isolated from WT, Foxo3a-/-, Il10-/- and Foxo3a-/-IL10-/- mice were used for flow cytometry, immunohistochemistry, ELISA, qRT-PCR and western blot techniques. Results Foxo3a restricts the expansion of the myeloid progenitors and mature cells, exacerbates inflammatory response in BM, regulates terminal differentiation and survival of myeloid cells, and also represses the accumulation of neutral lipids and metabolism in myeloid cells in Il10-deficient hosts. Conclusion Foxo3a attenuates the exacerbation of myelopoiesis in Il10-/- mice through the repression of Dgat2 and Calprotectin. Dgat2 catalyses the terminal step in triglyceride generation, leading to increased accumulation of neutral lipids, upregulation of cytokine expression and myelopoiesis. Funding Source NA Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)