The Inositol 3-Phosphatase PTEN Negatively Regulates Fcγ Receptor Signaling, but Supports Toll-Like Receptor 4 Signaling in Murine Peritoneal Macrophages

Abstract

FcγR clustering in macrophages activates signaling events that result in phagocytosis. Phagocytosis is accompanied by the generation harmful byproducts such as reactive oxygen radicals and production of inflammatory cytokines, which mandate that the phagocytic process be subject to a tight regulation. The molecular mechanisms involved in this regulation are not fully understood. In this study, we have examined the role of the inositol 3-phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in FcγR-induced macrophage function. We demonstrate that in ex vivo murine peritoneal macrophages that are deficient in PTEN expression, FcγR-induced Akt and extracellular signal-regulated kinase phosphorylation are enhanced. Notably, PTEN−/− macrophages showed constitutively high phosphorylation of Akt. However, PTEN did not seem to influence tyrosine phosphorylation events induced by FcγR clustering. Furthermore, PTEN−/− macrophages displayed enhanced phagocytic ability. Likewise, FcγR-induced production of TNF-α, IL-6, and IL-10 was significantly elevated in PTEN−/− macrophages. Surprisingly, LPS-induced TNF-α production was down-regulated in PTEN−/− macrophages. Analyzing the molecular events leading to PTEN influence on LPS/Toll-like receptor 4 (TLR4) signaling, we found that LPS-induced activation of mitogen-activated protein kinases is suppressed in PTEN−/− cells. Previous reports indicated that LPS-induced mitogen-activated protein kinase activation is down-regulated by phosphatidylinositol 3-kinase through the activation of Akt. Our observation that Akt activation is basally enhanced in PTEN−/− cells suggests that PTEN supports TLR4-induced inflammatory responses by suppressing the activation of Akt. Thus, we conclude that PTEN is a negative regulator of FcγR signaling, but a positive regulator of TLR4 signaling. These findings are the first to demonstrate a role for PTEN in FcγR- and TLR4-mediated macrophage inflammatory response.

OxLDL–IgG Immune Complexes Induce Survival of Human Monocytes

“…36 Of great interest, cross-linking of mouse Fc␥Rs with monoclonal antibodies has been shown to lead to PI 3-kinase activation and Akt phosphorylation. 37 Accordingly, we hypothesized that the anti-apoptotic effect of the OxLDL-IgG ICs was mediated either via secretion of M-CSF or via a direct effect of the ICs on Akt phosphorylation. Our finding of a rapid phosphorylation of Akt after addition of OxLDLIgG ICs and of inhibition of monocyte survival by blocking of the Akt pathway strongly support direct activation of Akt via Fc␥ receptors as the anti-apoptotic mechanism behind the immune complex-mediated survival.…”

Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K

“…PTENdeficient macrophages secreted decreased quantities of Tnf and Il6 upon stimulation with TLR ligands. 60,64,65 Consequently, in a pneumococcal pneumonia model, mice deficient for PTEN in the myeloid compartment have less Tnf, Il6 and Cxcl1 (also known as KC), but more Il10 in their bronchiolar lavage fluid. 66 This phenotype corresponded with increased phagocytosis and elimination of intracellular bacteria by alveolar macrophages infected in vitro with Streptococcus pneumonia.…”

The coordination of signaling during Fc receptor-mediated phagocytosis

“…Some of the many isoforms of membrane lipid-modifying enzymes contribute to FcR-mediated phagocytosis, including PI4P5K [34], PI-3K [67], PLA 2 [68], PLC [34], PLD [69], phosphatase and tensin homology deleted on chromosome 10 (PTEN) [70,71], and SHIP-1 [17,21]. The products of these enzymes can influence the activities of essential regulatory proteins [72].…”