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, A. Mócsai

Research output: Contribution to journalArticle

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Abstract

β2 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 β2 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 β2 integrin-mediated adherent activation, they showed mostly normal migration in β2 integrin-dependent in vitro and in vivo assays and normal β2 integrin-mediated killing of serum-opsonized Staphylococcus aureus and Escherichia coli. A neutrophil- and β2 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 β2 integrin-mediated in vitro and in vivo neutrophil functions or the effector phase of experimental autoimmune arthritis.

Original languageEnglish
Pages (from-to)3064-3075
Number of pages12
JournalJournal of Immunology
Volume185
Issue number5
DOIs
Publication statusPublished - Sep 1 2010

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Integrins
Arthritis
Neutrophils
Mutation
Bone Marrow
Experimental Arthritis
Monomeric GTP-Binding Proteins
Cell Surface Receptors
Liver Transplantation
Staphylococcus aureus
Signal Transduction
Fetus
Fibroblasts
Escherichia coli
Inflammation
Serum
Genes

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Neutrophil functions and autoimmune arthritis in the absence of p190RhoGAP : Generation and analysis of a novel null mutation in mice. / Németh, Tamás; Futosi, Krisztina; Hably, Csilla; Brouns, Madeleine R.; Jakob, Sascha M.; Kovács, Miklós; Kertész, Zsuzsanna; Walzog, Barbara; Settleman, Jeffrey; Mócsai, A.

In: Journal of Immunology, Vol. 185, No. 5, 01.09.2010, p. 3064-3075.

Research output: Contribution to journalArticle

Németh, T, Futosi, K, Hably, C, Brouns, MR, Jakob, SM, Kovács, M, Kertész, Z, Walzog, B, Settleman, J & Mócsai, A 2010, 'Neutrophil functions and autoimmune arthritis in the absence of p190RhoGAP: Generation and analysis of a novel null mutation in mice', Journal of Immunology, vol. 185, no. 5, pp. 3064-3075. https://doi.org/10.4049/jimmunol.0904163
Németh, Tamás ; Futosi, Krisztina ; Hably, Csilla ; Brouns, Madeleine R. ; Jakob, Sascha M. ; Kovács, Miklós ; Kertész, Zsuzsanna ; Walzog, Barbara ; Settleman, Jeffrey ; Mócsai, A. / Neutrophil functions and autoimmune arthritis in the absence of p190RhoGAP : Generation and analysis of a novel null mutation in mice. In: Journal of Immunology. 2010 ; Vol. 185, No. 5. pp. 3064-3075.
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AU - Mócsai, A.

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