We several projects. 1. A dogma of innate immunity is that neutrophils use chemoattractant GPCRs to chase bacteria through chemotaxis and then use phagocytic receptors coupled with tyrosine kinases to destroy opsonized bacteria via phagocytosis. Our current work has changed this dogma by showing that G-protein-coupled formyl peptide receptors (FPRs) directly mediate neutrophil phagocytosis. Mouse neutrophils lacking formyl peptide receptors (Fpr1/2-/-) are defective in the phagocytosis of E. coli and the chemoattractant fMLP-coated beads. fMLP immobilized on the surface of a bead interacts with FPRs triggers a Ca2+ response, and induces actin polymerization to form a phagocytic cup for engulfment of the bead. Chemoattractant GPCR/Gi signaling and phagocytic receptor/tyrosine kinase signaling work independently to promote phagocytosis of beads coated with either chemoattractants or IgG opsonins. Thus, in addition to phagocytic receptor-mediated phagocytosis, neutrophils also utilize the chemoattractant GPCR/Gi signaling to mediate phagocytosis to fight invading bacteria (Wen etal, in revision). 2. Neutrophils sense and migrate through a large range of chemoattractant gradient through an adaptation mechanism. Here, we reveal CPARI, a negative regulator of Ras, that controls GPCR-stimulated Ras signaling in human neutrophils. Cells lacking CAPRI (caprikd) exhibit significantly increased phosphorylation of AKT, GSK3, and cofilin, leading to excessive actin polymerization and subsequent defects in neutrophil chemotaxis. The caprikd cells display chemotaxis defects only in high concentration, but not in low-concentration gradient, remarkably, show better chemotaxis in sub-responsive concentration of chemoattractant gradient due to their higher sensitivity. Taken together, we reveal that CAPRI controls GPCR-mediated adaptation and downshifts the sensitivity of neutrophils for Chemotaxis.

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8
Fiscal Year
2018
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Gera, Nidhi; Swanson, Kenneth D; Jin, Tian (2017) ?-Arrestin 1-dependent regulation of Rap2 is required for fMLP-stimulated chemotaxis in neutrophil-like HL-60 cells. J Leukoc Biol 101:239-251
Xu, Xuehua; Yun, Michelle; Wen, Xi et al. (2016) Quantitative Monitoring Spatiotemporal Activation of Ras and PKD1 Using Confocal Fluorescent Microscopy. Methods Mol Biol 1407:307-23
Wang, Youhong; Xu, Xuehua; Pan, Miao et al. (2016) ELMO1 Directly Interacts with G?? Subunit to Transduce GPCR Signaling to Rac1 Activation in Chemotaxis. J Cancer 7:973-83
Wang, Gang; Cao, Luyang; Liu, Xiaowen et al. (2016) Oxidant Sensing by TRPM2 Inhibits Neutrophil Migration and Mitigates Inflammation. Dev Cell 38:453-62
Xu, Xuehua; Gera, Nidhi; Li, Hongyan et al. (2015) GPCR-mediated PLC??/PKC?/PKD signaling pathway regulates the cofilin phosphatase slingshot 2 in neutrophil chemotaxis. Mol Biol Cell 26:874-86
Li, Hongyan; Yang, Lei; Fu, Hui et al. (2013) Association between Gýýi2 and ELMO1/Dock180 connects chemokine signalling with Rac activation and metastasis. Nat Commun 4:1706
Guo, Jia; Xu, Xuehua; Rasheed, Taban K et al. (2013) Genistein interferes with SDF-1- and HIV-mediated actin dynamics and inhibits HIV infection of resting CD4 T cells. Retrovirology 10:62
Guo, Jia; Xu, Xuehua; Yuan, Wen et al. (2012) HIV gp120 is an aberrant chemoattractant for blood resting CD4 T cells. Curr HIV Res 10:636-42
Chen, Yan; Yue, Shen; Xie, Lu et al. (2011) Dual Phosphorylation of suppressor of fused (Sufu) by PKA and GSK3beta regulates its stability and localization in the primary cilium. J Biol Chem 286:13502-11
Kim, Jung-Sik; Xu, Xuehua; Li, Huifang et al. (2011) Mechanistic analysis of a DNA damage-induced, PTEN-dependent size checkpoint in human cells. Mol Cell Biol 31:2756-71