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G?i1 and G?i3 regulate macrophage polarization by forming a complex containing CD14 and Gab1.

ABSTRACT: 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?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?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?i1/3 deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). G?i1/3 knockdown in bone marrow-derived macrophage cells (G?i1/3 KD BMDMs) exhibited an M2-like phenotype with significantly suppressed production of TNF-?, IL-6, IL-12, and NO in response to LPS. The altered polarization coincided with decreased Akt activation. Further, G?i1/3 deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, G?i1/3 were down-regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that G?i1/3 can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo.

SUBMITTER: Li X

PROVIDER: S-EPMC4403188 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Gαi1 and Gαi3 regulate macrophage polarization by forming a complex containing CD14 and Gab1.

Li Xianjing X Wang Duowei D Chen Zhen Z Lu Ermei E Wang Zhuo Z Duan Jingjing J Tian Wei W Wang Yun Y You Linjun L Zou Yulian Y Cheng Yan Y Zhu Qingyi Q Wan Xiaojian X Xi Tao T Jiang Meisheng M Han Yuyuan Y Cao Cong C Birnbaumer Lutz L Chu Wen-Ming WM Yang Yong Y

Proceedings of the National Academy of Sciences of the United States of America 20150330 15

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 (Gαi1/3) 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, Gαi1/3 form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb ...[more]

PMID: 25825741

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Project description:Macrophages (Mφ) are immune cells that exhibit remarkable functional plasticity. Identification of novel endogenous factors that can regulate plasticity and innate immune functions of Mφ will unravel new strategies to curb immune-related diseases. Long non-coding RNAs (lncRNAs) are a class of endogenous, non-protein coding, regulatory RNAs that are increasingly being associated with various cellular functions and diseases. Despite their ubiquity and abundance, lncRNA-mediated epigenetic regulation of Mφ polarization and innate immune functions is poorly studied. This study elucidates the regulatory role of lncRNAs in monocyte to Mφ differentiation, M1/M2 dichotomy and innate immune responses. Expression profiling of eighty-eight lncRNAs in monocytes and in vitro differentiated M2 Mφ identified seventeen differentially expressed lncRNAs. Based on fold-change and significance, we selected four differentially expressed lncRNAs viz., RN7SK, GAS5, IPW, and ZFAS1 to evaluate their functional impact. LncRNA knockdown was performed on day 3 M2 Mφ and the impact on polarization was assessed on day 7 by surface marker analysis. Knockdown of RN7SK and GAS5 showed downregulation of M2 surface markers (CD163, CD206, or Dectin) and concomitant increase in M1 markers (MHC II or CD23). RN7SK or GAS5 knockdown showed no significant impact on CD163, CD206, or CD23 transcripts. M1/M2 markers were not impacted by IPW or ZFAS1 knockdown. Functional regulation of antigen uptake/processing and phagocytosis, two central innate immune pathways, by candidate lncRNA was assessed in M1/M2 Mφ. Compared to scramble, enhanced antigen uptake and processing were observed in both M1/M2 Mφ transfected with siRNA targeting GAS5 and RN7SK but not IPW and ZFAS1. In addition, knockdown of RN7SK significantly augmented uptake of labelled E. coli in vitro by M1/M2 Mφ, while no significant difference was in GAS5 silencing cells. Together, our results highlight the instrumental role of lncRNA (RN7SK and GAS5)-mediated epigenetic regulation of macrophage differentiation, polarization, and innate immune functions.

Dataset Information

G?i1 and G?i3 regulate macrophage polarization by forming a complex containing CD14 and Gab1.

Publications

Gαi1 and Gαi3 regulate macrophage polarization by forming a complex containing CD14 and Gab1.

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