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ATF3 regulates neutrophil migration in mice

Boespflug, Nicholas
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1382372804

Abstract Details

2013, PhD, University of Cincinnati, Medicine: Immunology.
Activating transcription factor 3 (ATF3) is a counter-regulatory immune transcription factor whose expression is induced by Toll-like receptor (TLR) signaling. In turn, ATF3 inhibits the expression of various TLR-driven pro-inflammatory genes. In response to low-dose or transient pro-inflammatory stimulation, ATF3 attenuates immune activation, yet ATF3 silences its own transcription after high-dose or persistent stimulation, facilitating immune activation under these conditions. Given its counter-regulatory role in diverse innate immune responses, we defined the effects of ATF3 on neutrophilic airway inflammation in mice. Genetic deletion of ATF3 was associated with increased lipopolysaccharide (LPS)-driven airway epithelia production of CXCL1, concordant with the presence of a consensus ATF3-binding site identified in the Cxcl1 promoter. Unexpectedly, ATF3-deficient mice did not exhibit increased airway neutrophilia after LPS challenge. Bone marrow chimeras revealed a specific reduction in ATF3-/- neutrophil recruitment to wild type lungs, while in vitro studies revealed a profound ATF3-/- neutrophil-intrinsic chemotaxis defect. Global gene expression analysis identified an absence of Tiam2 expression in ATF3-/- neutrophils. Kinetic mRNA analysis of human neutrophil development revealed ATF3 and TIAM2 expression patterns consistent with positive TIAM2 regulation by ATF3 during neutrophil development. TIAM2 regulates cellular motility by activating Rac1-mediated focal adhesion disassembly. Correspondingly, ATF3-/- neutrophils lacking TIAM2 exhibited increased focal complex area, along with excessive CD11b-mediated F-actin polymerization. The exact molecular mechanism(s) of ATF3 regulation of Tiam2 expression and TIAM2-mediated cellular translocation are currently under investigation. Together, these findings implicate ATF3 as an important functional and developmental regulator of neutrophils. However, the effects of the ATF3/TIAM2 axis on chemotaxis may extend beyond neutrophils, as loss of ATF3 can confer metastatic potential on non-metastatic cancers cell lines. Further, preliminary experiments have investigated the effect of ATF3 on immune responses in infectious models. ATF3-/- mice exhibit reducedToxoplasma gondii cyst burden without the attendant increase in mortality seen with deletion of other counter-regulatory pathways. Additionally, ATF3 is induced by infection with persistent sub-strains of lymphocytic choriomeningitis virus (LCMV), and ATF3-/- mice exhibit modest reductions in viral burdens due to such strains. In total, this work reinforces the counter-regulatory nature of ATF3 in the setting of immune responses, and defines novel functions for ATF3 in neutrophil biology. This makes ATF3 and downstream effector molecules attractive potential therapeutic candidates for diseases associated with excessive or detrimental neutrophil recruitment, and/or chronic viral or parasitic infections.
Christopher Karp, M.D. (Committee Chair)
Marie-Dominique Filippi, Ph.D. (Committee Member)
H. Leighton Grimes, Ph.D. (Committee Member)
John Clancy, M.D. (Committee Member)
David Hildeman, Ph.D. (Committee Member)
Kasper Hoebe, Ph.D. (Committee Member)
276 p.
Immunology
ATF3; neutrophil; recruitment; TIAM2; focal adhesion; chemotaxis

Recommended Citations

Citations

  • Boespflug, N. (2013). ATF3 regulates neutrophil migration in mice [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1382372804

    APA Style (7th edition)

  • Boespflug, Nicholas. ATF3 regulates neutrophil migration in mice. 2013. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1382372804.

    MLA Style (8th edition)

  • Boespflug, Nicholas. "ATF3 regulates neutrophil migration in mice." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1382372804

    Chicago Manual of Style (17th edition)

ucin1382372804
819
© 2013, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.