Neutrophil functions and autoimmune arthritis in the absence of p190RhoGAP: generation and analysis of a novel null mutation in mice

Tamás Németh, Krisztina Futosi, Csilla Hably, Madeleine R Brouns, Sascha M Jakob, Miklós Kovács, Zsuzsanna Kertész, Barbara Walzog, Jeffrey Settleman, Attila Mócsai

    Research output: Contribution to JournalArticleAcademicpeer-review

    Abstract

    Beta(2) integrins of neutrophils play a critical role in innate immune defense, but they also participate in tissue destruction during autoimmune inflammation. p190RhoGAP (ArhGAP35), a regulator of Rho family small GTPases, is required for integrin signal transduction in fibroblasts. Prior studies have also suggested a role for p190RhoGAP in beta(2) integrin signaling in neutrophils. To directly test that possibility, we have generated a novel targeted mutation completely disrupting the p190RhoGAP-encoding gene in mice. p190RhoGAP deficiency led to perinatal lethality and defective neural development, precluding the analysis of neutrophil functions in adult p190RhoGAP(-/-) animals. This was overcome by transplantation of fetal liver cells from p190RhoGAP(-/-) fetuses into lethally irradiated wild-type recipients. Neutrophils from such p190RhoGAP(-/-) bone marrow chimeras developed normally and expressed normal levels of various cell surface receptors. Although p190RhoGAP(-/-) neutrophils showed moderate reduction of beta(2) integrin-mediated adherent activation, they showed mostly normal migration in beta(2) integrin-dependent in vitro and in vivo assays and normal beta(2) integrin-mediated killing of serum-opsonized Staphylococcus aureus and Escherichia coli. A neutrophil- and beta(2) integrin-dependent transgenic model of the effector phase of autoimmune arthritis also proceeded normally in p190RhoGAP(-/-) bone marrow chimeras. In contrast, all the above responses were completely blocked in CD18(-/-) neutrophils or CD18(-/-) bone marrow chimeras. These results suggest that p190RhoGAP likely does not play a major indispensable role in beta(2) integrin-mediated in vitro and in vivo neutrophil functions or the effector phase of experimental autoimmune arthritis.

    Original languageEnglish
    Pages (from-to)3064-75
    Number of pages12
    JournalJournal of Immunology
    Volume185
    Issue number5
    DOIs
    Publication statusPublished - 1 Sep 2010

    Keywords

    • Animals
    • Arthritis, Experimental/enzymology
    • Autoimmune Diseases/enzymology
    • Bone Marrow Cells/immunology
    • CD18 Antigens/physiology
    • Cells, Cultured
    • Clone Cells
    • Disease Models, Animal
    • GTPase-Activating Proteins/deficiency
    • Guanine Nucleotide Exchange Factors/deficiency
    • Humans
    • Mice
    • Mice, Inbred C57BL
    • Mice, Knockout
    • Mice, Transgenic
    • Mutation/immunology
    • Neutrophils/enzymology
    • Repressor Proteins/deficiency

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