Forkhead Box O1 Regulates Macrophage Polarization Following Staphylococcus aureus Infection: Experimental Murine Data and Review of the Literature

Abstract

The functions of macrophages that lead to effective host responses are critical for protection against Staphylococcus aureus. Deep tissue-invading S. aureus initially countered by macrophages trigger macrophage accumulation and induce inflammatory responses through surface receptors, especially toll-like receptor 2 (TLR2). Here, we found that macrophages formed sporadic aggregates in the liver during infection. Within those aggregates, macrophages co-localized with T cells and were indispensable for their infiltration. In addition, we have focused on the mechanisms underlying the polarization of macrophages in Forkhead box transcription factor O1 (FoxO1) conditional knockout Lys FoxO1 mice following S. aureus infection and report herein that macrophage M1-M2 polarization via TLR2 is intrinsically regulated by FoxO1. Indeed, for effective FoxO1 activity, stimulation of TLR2 is essential. However, following S. aureus challenge, there was a decrease in macrophage FoxO1, with increased phosphorylation of FoxO1 because of TLR2-mediated activation of PI3K/Akt and c-Raf/MEK/ERK pathway. Following infection in Lys FoxO1 mice, mice became more susceptible to S. aureus with reduced macrophage aggregation in the liver and attenuated Th1 and Th17 responses. FoxO1 abrogation reduced M1 pro-inflammatory responses triggered by S. aureus and enhanced M2 polarization in macrophages. In contrast, overexpression of FoxO1 in macrophages increased pro-inflammatory mediators and functional surface molecule expression. In conclusion, macrophage FoxO1 is critical to promote M1 polarization and maintain a competent T cell immune response against S. aureus infection in the liver. FoxO1 regulates macrophage M1-M2 polarization downstream of TLR2 dynamically through phosphorylation.

Lipotoxic Hepatocyte‐Derived Exosomal MicroRNA 192‐5p Activates Macrophages Through Rictor/Akt/Forkhead Box Transcription Factor O1 Signaling in Nonalcoholic Fatty Liver Disease

“…(12) Previous studies in FoxO1 conditional knockout mice identified an important role of FoxO1 in macrophage polarization in the liver. (13) Furthermore, Rictor is one of the four predicted target genes of miR-192-5p in both humans and rodents. Therefore, the Rictor-Akt-FoxO1 axis may represent a key signaling pathway underlying miR-192-5pmediated M1 polarization and activation of macrophages in NAFLD.…”

“…(12) In macrophages, FoxO1 has been identified to regulate macrophage polarization and activation through up-regulating toll-like receptormediated signaling. (13,35) Our results suggest that miR-192-5p promotes an inflammatory response in macrophages at least partially through its negative regulation of the Rictor/Akt/FoxO1 signaling pathway.…”

Modulation of liver regeneration via myeloid PTEN deficiency

“…13 In line with these findings, our previous study showed that macrophage FoxO1 was important in promoting M1 macrophage polarization. 15 In this study, significantly higher activation levels of Akt and lower activation levels of FoxO1 were determined in the Kupffer cells of PTEN mKO mice (Supplementary Figure 6). Thus, it is possible that in PTEN mKO mice, PTEN deficiency enhanced Akt/FoxO1 signaling in macrophages.…”

“…In addition, PTEN mKO mice showed significantly higher levels of phosphorylated Akt and FoxO1 compared with PTEN f/f mice ( P =0.0480 for p-Akt and P =0.0003 for p-FoxO1, Supplementary Figure 6). Considering that activated Akt signaling and thus inhibited FoxO1 signaling was involved in suppressing proinflammatory cytokine secretion and promoting M2-like polarization of macrophages, 13, 15 this result indicated that PTEN may regulate the polarization of Kupffer cells through downstream Akt/FoxO1 signaling pathway.…”

Multi-omics analysis identifies FoxO1 as a regulator of macrophage function through metabolic reprogramming

“…Besides FoxO1 also interacts with the Toll-like receptor 4-mediated inflammatory response 35 and regulates IL-10 secretion during classic activation in hyperglycemia 36 . In previous studies, we found that FoxO1 regulates macrophage polarization in infection and promotes the anti-tumor function of TAMs by upregulating major histocompatibility complex II (MHC-II) expression 37,38 . In this study, we focused on the transcriptional mechanism of macrophage metabolic reprogramming.…”