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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 (G alpha(i1/3)) 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, G alpha(i1/3) 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. G alpha(i1/3) deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). G alpha(i1/3) knockdown in bone marrow-derived macrophage cells (G alpha(i1/3) 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 coincidedwith decreased Akt activation. Further, G alpha(i1/3) deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, G alpha(i1/3) were down-regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that G alpha(i1/3) can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo.