Mucosal Immunity and the FOXO1 Transcription Factors

Abstract

FOXO1 transcription factors affect a number of cell types that are important in the host response. Cell types whose functions are modulated by FOXO1 include keratinocytes in the skin and mucosal dermis, neutrophils and macrophages, dendritic cells, Tregs and B-cells. FOXO1 is activated by bacterial or cytokine stimulation. Its translocation to the nucleus and binding to promoter regions of genes that have FOXO response elements is stimulated by the MAP kinase pathway and inhibited by the PI3 kinase/AKT pathway. Downstream gene targets of FOXO1 include pro-inflammatory signaling molecules (TLR2, TLR4, IL-1β, and TNF-α), wound healing factors (TGF-β, VEGF, and CTGF) adhesion molecules (integrins-β1, -β3, -β6, αvβ3, CD11b, CD18, and ICAM-1), chemokine receptors (CCR7 and CXCR2), B cell regulators (APRIL and BLYS), T-regulatory modulators (Foxp3 and CTLA-4), antioxidants (GPX-2 and cytoglobin), and DNA repair enzymes (GADD45α). Each of the above cell types are found in oral mucosa and modulated by bacteria or an inflammatory microenvironment. FOXO1 contributes to the regulation of these cells, which collectively maintain and repair the epithelial barrier, formation and activation of Tregs that are needed to resolve inflammation, mobilization, infiltration, and activation of anti-bacterial defenses in neutrophils, and the homing of dendritic cells to lymph nodes to induce T-cell and B-cell responses. The goal of the manuscript is to review how the transcription factor, FOXO1, contributes to the activation and regulation of key leukocytes needed to maintain homeostasis and respond to bacterial challenge in oral mucosal tissues. Examples are given with an emphasis on lineage specific deletion of Foxo1 to explore the impact of FOXO1 on cell behavior, inflammation and susceptibility to infection.

Identification of prognostic factors for intrahepatic cholangiocarcinoma using long non-coding RNAs-associated ceRNA network

“…FOXO1 transcription factors orchestrate various cell types that are important in the host response [37]. Moreover, FOXO1 has been described to assume a pivotal role in tumor initiation, progression and metastasis [38].…”

Apremilast Regulates the Teff/Treg Balance to Ameliorate Uveitis via PI3K/AKT/FoxO1 Signaling Pathway

“…It is interesting to explore whether, in experimental AU (EAU), apremilast could influence the PI3K/AKT pathway. In addition, transcription factor forkhead-box O1 (FoxO1), among the FoxO family in mammals, is modulated mainly by the PI3K/AKT signal via phosphorylation (22), and FoxO1 has been reported to regulate several downstream gene targets including pro-inflammatory molecules, adhesion molecules, B-cell regulators, and Tregulatory modulators (23). It has been recently shown to increase Foxp3 expression of CD4+ T-cells and strengthen the population and capability of Treg cells (24).…”

Evidence that Maackia amurensis seed lectin (MASL) exerts pleiotropic actions on oral squamous cells to inhibit SARS-CoV-2 infection and COVID-19 disease progression

“…Accordingly, NF-kB signaling has been implicated in the control of ACE2 expression and COVID-19 inflammatory pathologies 34,45,46 . If left unchecked, these infections induce FOXO1 expression in epithelial cells including oral mucosa, which induces the expression of toll-like receptors (TLRs) 47 . TLR signaling induces interleukin-36 (IL36) production, which induces IL6 expression 48 .…”