| First Author | Li X | Year | 2015 |
| Journal | Proc Natl Acad Sci U S A | Volume | 112 |
| Issue | 15 | Pages | 4731-6 |
| PubMed ID | 25825741 | Mgi Jnum | J:220534 |
| Mgi Id | MGI:5635312 | Doi | 10.1073/pnas.1503779112 |
| Citation | Li X, et al. (2015) Galphai1 and Galphai3 regulate macrophage polarization by forming a complex containing CD14 and Gab1. Proc Natl Acad Sci U S A 112(15):4731-6 |
| abstractText | Heterotrimeric G proteins have been implicated in Toll-like receptor 4 (TLR4) signaling in macrophages and endothelial cells. However, whether guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Galphai1/3) are required for LPS responses remains unclear, and if so, the underlying mechanisms need to be studied. In this study, we demonstrated that, in response to LPS, Galphai1/3 form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling. Galphai1/3 deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). Galphai1/3 knockdown in bone marrow-derived macrophage cells (Galphai1/3 KD BMDMs) exhibited an M2-like phenotype with significantly suppressed production of TNF-alpha, IL-6, IL-12, and NO in response to LPS. The altered polarization coincided with decreased Akt activation. Further, Galphai1/3 deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, Galphai1/3 were down-regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that Galphai1/3 can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo. |
