Abstract
Gene expression can be regulated by chromatin modifiers, transcription factors and proteins that modulate DNA architecture. Among the latter, AT-hook transcription factors have emerged as multifaceted regulators that can activate or repress broad A/T-rich gene networks. Thus, alterations of AT-hook genes could affect the transcription of multiple genes causing global cell dysfunction. Here we report that targeted deletions of mouse AKNA, a hypothetical AT-hook-like transcription factor, sensitize mice to pathogen-induced inflammation and cause sudden neonatal death. Compared with wild-type littermates, AKNA KO mice appeared weak, failed to thrive and most died by postnatal day 10. Systemic inflammation, predominantly in the lungs, was accompanied by enhanced leukocyte infiltration and alveolar destruction. Cytologic, immunohistochemical and molecular analyses revealed CD11b+Gr1+ neutrophils as major tissue infiltrators, neutrophilic granule protein, cathelin-related antimicrobial peptide and S100A8/9 as neutrophil-specific chemoattracting factors, interleukin-1β and interferon-γ as proinflammatory mediators, and matrix metalloprotease 9 as a plausible proteolytic trigger of alveolar damage. AKNA KO bone marrow transplants in wild-type recipients reproduced the severe pathogen-induced reactions and confirmed the involvement of neutrophils in acute inflammation. Moreover, promoter/reporter experiments showed that AKNA could act as a gene repressor. Our results support the concept of coordinated pathway-specific gene regulation functions modulating the intensity of inflammatory responses, reveal neutrophils as prominent mediators of acute inflammation and suggest mechanisms underlying the triggering of acute and potentially fatal immune reactions.
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Acknowledgements
We thank Dr Shao-Cong Sun and Dr Yong-Jun Liu (The University of Texas MD Anderson Cancer Center, USA) for their critiques and advice. We also thank Dr Douglas D Boyd (The University of Texas MD Anderson Cancer Center, USA) and Dr Richard L Gallo (University of California, San Diego, USA) for their generosity in providing the MMP9 promoter/Luciferase reporter and the anti-CRAMP antibody, respectively. The present work was supported by grants AI056125-01 and AI065796-01 from the National Institutes of Health (NIH) and by NCI CCSG Core grant CA106672. MRM was supported by the training grant T32 CA009598-15 from the NIH and WM was supported by the Odyssey Program and The Cockrell Foundation Award for Scientific Achievement at The University of Texas MD Anderson Center Cancer.
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
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Supplementary information, Figure S1
AKNA Genotype and expression analyses. (PDF 1205 kb)
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Comparative assessment of alveolar airspace. (PDF 62 kb)
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Lung Elastin deposit, cytokine expression and apoptosis. (PDF 16935 kb)
Supplementary information, Figure S4
Circulating lymphocytes and lung cytokine expression. (PDF 89 kb)
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Ma, W., Ortiz-Quintero, B., Rangel, R. et al. Coordinate activation of inflammatory gene networks, alveolar destruction and neonatal death in AKNA deficient mice. Cell Res 21, 1564–1577 (2011). https://doi.org/10.1038/cr.2011.84
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DOI: https://doi.org/10.1038/cr.2011.84
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