ATF3 is a novel regulator of mouse neutrophil migration.
Expression of the activating transcription factor 3 (ATF3) gene is induced by Toll-like receptor (TLR) signaling. In turn, ATF3 protein inhibits the expression of various TLR-driven proinflammatory genes. Given its counter-regulatory role in diverse innate immune responses, we defined the effects of ATF3 on neutrophilic airway inflammation in mice. ATF3 deletion was associated with increased lipopolysaccharide (LPS)-driven airway epithelia production of CXCL1, but not CXCL2, findings concordant with a consensus ATF3-binding site identified solely 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. In vitro, ATF3(-/-) neutrophils exhibited a profound chemotaxis defect. Global gene expression analysis identified ablated Tiam2 expression in ATF3(-/-) neutrophils. TIAM2 regulates cellular motility by activating Rac1-mediated focal adhesion disassembly. Notably, ATF3(-/-) and ATF3-sufficient TIAM2 knockdown neutrophils, both lacking TIAM2, exhibited increased focal complex area, along with excessive CD11b-mediated F-actin polymerization. Together, our data describe a dichotomous role for ATF3-mediated regulation of neutrophilic responses: inhibition of neutrophil chemokine production but promotion of neutrophil chemotaxis.
Division of Cellular and Molecular Immunology, and.
Nicholas D
ND
Boespflug
Sachin
S
Kumar
Jaclyn W
JW
McAlees
James D
JD
Phelan
H Leighton
HL
Grimes
Kasper
K
Hoebe
Tsonwin
T
Hai
Marie-Dominique
MD
Filippi
Christopher L
CL
Karp
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism; D007154:Immune System Diseases / Q000235:genetics*; D007960:Leukocyte Disorders / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D054360:Chemokine CXCL1; D008070:Lipopolysaccharides