SHIP-1 Regulates Phagocytosis and M2 Polarization Through the PI3K/Akt–STAT5–Trib1 Circuit in Pseudomonas aeruginosa Infection

Abstract

SHIP-1 is an inositol phosphatase that hydrolyzes phosphatidylinositol 3-kinase (PI3K) products and negatively regulates protein kinase B (Akt) activity, thereby modulating a variety of cellular processes in mammals. However, the role of SHIP-1 in bacterial-induced sepsis is largely unknown. Here, we show that SHIP-1 regulates inflammatory responses during Gram-negative bacterium Pseudomonas aeruginosa infection. We found that infected-SHIP-1 −/− mice exhibited decreased survival rates, increased inflammatory responses, and susceptibility owing to elevated expression of PI3K than wild-type (WT) mice. Inhibiting SHIP-1 via siRNA silencing resulted in lipid raft aggregates, aggravated oxidative damage, and bacterial burden in macrophages after PAO1 infection. Mechanistically, SHIP-1 deficiency augmented phosphorylation of PI3K and nuclear transcription of signal transducer and activator of transcription 5 (STAT5) to induce the expression of Trib1, which is critical for differentiation of M2 but not M1 macrophages. These findings reveal a previously unrecognized role of SHIP-1 in inflammatory responses and macrophage homeostasis during P. aeruginosa infection through a PI3K/Akt-STAT5-Trib1 axis.

ELOVL5-Mediated Long Chain Fatty Acid Elongation Contributes to Enzalutamide Resistance of Prostate Cancer

“…To directly confirm the link between ELOLV5 and AKT-mTOR signaling, the AKT inhibitor (LY294002) was used to treat ELOVL5 expressing LNCaP/AR cells and was shown to enhance the enzalutamide sensitivity of ELOVL5-expressing LNCaP/AR cells (Figure B). Lipid raft has been reported as an important membrane microdomain for AKT activation [28]. The formation of lipid rafts were measured by lipid raft assay kit (Vybrant™ Alexa Fluor™ 555, V34404) and the numbers of lipid rafts were increased in ELOVL5 expressing cells (Figure C, p < 0.0001).…”

Construction of a ceRNA Network and Analysis of Tumor Immune Infiltration in Pancreatic Adenocarcinoma

“…The number of CD8 + T cells in the tumor microenvironment in pancreatic and breast cancers is important for response prediction after chemotherapy and immunotherapy ( Meyer et al, 2018 ). M2 macrophages and pro-inflammatory M1 macrophages are associated with the growth and diffusion of tumors and the formation of an immunosuppressive microenvironment ( Tsuboi et al, 2019 ; Qin et al, 2020 ). The oncogenic role of M1 macrophages in most malignancies has been found.…”

Polarized Macrophages in Periodontitis: Characteristics, Function, and Molecular Signaling

“…Since P13K is the most important upstream molecule of PIP3/PDK/P13K, this signaling pathway is also known as the P13K/Akt signaling pathway. The role of the PI3K/Akt signaling pathway in macrophage polarization has gradually received attention and has been confirmed to mediate the transformation of M2 (155,156). Guo et al demonstrated that the absence of GaB1 or GaB2 in Gab family adapters leads to impaired M2 polarization, while IL-4 regulates the polarization of M2 by activating GAB1 to induce the Akt signaling pathway (157).…”