Coordinate activation of inflammatory gene networks, alveolar destruction and neonatal death in AKNA deficient mice

作者：Ma Wenbin; Ortiz Quintero Blanca; Rangel Roberto; McKeller Morgan R; Herrera Rodriguez Sara; Castillo Eliseo F; Schluns Kimberly S; Hall Mary; Zhang Huiyuan; Suh Woong Kyung; Okada Hitoshi; Mak Tak W; Zhou Yang; Blackburn Michael R; Martinez Valdez Hector^*

来源：Cell Research, 2011, 21(11): 1564-1577.

DOI：10.1038/cr.2011.84

• in vivo
• mouse genetics
• gene network regulation
• inflammation
• pathogens
• innate reactions

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-1 beta and interferon-gamma as proinflammatory mediators, and matrix metalloprotease 9 as a plausible proteolytic trigger of alveolar damage. AKNA KO bone marrow transplants in wildtype 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.

• 出版日期2011-11