FoxO Transcription Factors: Applicability as a Novel Immune Cell Regulators and Therapeutic Targets in Oxidative Stress-Related Diseases

Abstract

Forkhead box O transcription factors (FoxOs) play an important role in maintaining normal cell physiology by regulating survival, apoptosis, autophagy, oxidative stress, the development and maturation of T and B lymphocytes, and the secretion of inflammatory cytokines. Cell types whose functions are regulated by FoxOs include keratinocytes, mucosal dermis, neutrophils, macrophages, dendritic cells, tumor-infiltrating activated regulatory T (Tregs) cells, B cells, and natural killer (NK) cells. FoxOs plays a crucial role in physiological and pathological immune responses. FoxOs control the development and function of Foxp3+ Tregs. Treg cells and Th17 cells are subsets of CD4+ T cells, which play an essential role in immune homeostasis and infection. Dysregulation of the Th17/Treg cell balance has been implicated in the development and progression of several disorders, such as autoimmune diseases, inflammatory diseases, and cancer. In addition, FoxOs are stimulated by the mitogen-activated protein (MAP) kinase pathway and inhibited by the PI3 kinase/AKT pathway. Downstream target genes of FoxOs include pro-inflammatory signaling molecules (toll-like receptor (TLR) 2, TLR4, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α), chemokine receptors (CCR7 and CXCR2), B-cell regulators (APRIL and BLYS), T-regulatory modulators (Foxp3 and CTLA-4), and DNA repair enzymes (GADD45α). Here, we review the recent progress in our understanding of FoxOs as the key molecules involved in immune cell differentiation and its role in the initiation of autoimmune diseases caused by dysregulation of immune cell balance. Additionally, in various diseases, FoxOs act as a cancer repressor, and reviving the activity of FoxOs forces Tregs to egress from various tissues. However, FoxOs regulate the cytotoxicity of both CD8+ T and NK cells against tumor cells, aiding in the restoration of redox and inflammatory homeostasis, repair of the damaged tissue, and activation of immune cells. A better understanding of FoxOs regulation may help develop novel potential therapeutics for treating immune/oxidative stress-related diseases.

Metadichol® a Sirtuin Modulator for Anti-Aging Therapies

“…These substrates are involved in various cellular processes, such as glucose metabolism, lipid metabolism, oxidative stress, cell cycle arrest, and apoptosis. FOXO1 has been implicated (37)(38)(39)(40) in the pathogenesis and prevention of various diseases, such as diabetes, obesity, cardiovascular diseases, neurodegenerative diseases, and cancers. For example, FOXO1 can improve insulin sensitivity and glucose homeostasis by regulating gluconeogenic enzymes, and GLUT4 expression can inhibit adipogenesis and lipogenesis by suppressing PPARγ and SREBP-1c expression.…”

Metadichol® a Sirtuin Modulator for Anti-Aging Therapies

“…These substrates are involved in various cellular processes, such as glucose metabolism, lipid metabolism, oxidative stress, cell cycle arrest, and apoptosis. FOXO1 has been implicated (37)(38)(39)(40) in the pathogenesis and prevention of various diseases, such as diabetes, obesity, cardiovascular diseases, neurodegenerative diseases, and cancers. For example, FOXO1 can improve insulin sensitivity and glucose homeostasis by regulating gluconeogenic enzymes, and GLUT4 expression can inhibit adipogenesis and lipogenesis by suppressing PPARγ and SREBP-1c expression.…”

Association of FOXO3A with right ventricular myocardial fibrosis and its detection by speckle‐tracking echocardiography in pulmonary hypertension

“…FOXO3A is a core regulator involved in the modulation of various physiological and pathological processes, including oxidative stress, proliferation, differentiation, apoptosis, and metabolism. 24 It has been reported that decreased FOXO3A expression was associated with enhanced cardiac fibrosis in peripartum cardiomyopathy, which is closely related to the promoting antioxidative defense function of FOXO3A. 25 Additionally, FOXO3A also has a role in inhibiting cardiac fibroblast hyperplasia by promoting p27 expression.…”