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

• Published in: Frontiers in immunology Vol. 11; p. 307
• Main Authors: Qin, Shugang, Li, Jiaxin, Zhou, Chuanmin, Privratsky, Breanna, Schettler, Jacob, Deng, Xin, Xia, Zhenwei, Zeng, Yong, Wu, Hong, Wu, Min
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 18.03.2020
• Subjects: Akt; Animals; Cell Polarity; Immunology; Intracellular Signaling Peptides and Proteins - physiology; M1 macrophages; Macrophages - immunology; Macrophages - physiology; Mice; Mice, Inbred C57BL; Phagocytosis; Phosphatidylinositol 3-Kinases - physiology; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - physiology; Phosphorylation; PI3K; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - physiology; Proto-Oncogene Proteins c-akt - physiology; Pseudomonas aeruginosa; Pseudomonas Infections - immunology; SHIP-1; STAT5; STAT5 Transcription Factor - physiology; M2 macrophage; PI3K; M1 macrophages; Pseudomonas aeruginosa; STAT5; Akt; SHIP-1
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.00307

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 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 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 infection through a PI3K/Akt-STAT5-Trib1 axis.