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Activating transcription factor 3 contributes to Toll-like receptor-mediated macrophage survival via repression of

Matthew R Thompson1, Dakang Xu, Bryan R G Williams

  • 1Monash Institute of Medical Research, Monash University , Clayton, Victoria, Australia .

Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research
|May 24, 2013
PubMed

Insights

Activating transcription factor 3 (ATF3) is crucial for macrophage survival during innate immune responses. This study reveals ATF3 suppresses apoptosis by regulating pro-apoptotic genes, highlighting its role in preventing excessive inflammation.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Macrophages are vital for innate immunity but excessive activation drives chronic inflammation.
  • Toll-like receptors (TLRs) regulate macrophage immune responses, promoting survival and resisting apoptosis.
  • Activating transcription factor 3 (ATF3) previously identified as a negative regulator of pro-inflammatory cytokine transcription.

Purpose of the Study:

  • To investigate the novel role of ATF3 in Toll-like receptor (TLR)-mediated macrophage survival.
  • To determine if ATF3 is required for suppressing apoptosis in macrophages upon TLR stimulation.

Main Methods:

  • Utilized ATF3-deficient bone marrow-derived macrophages.
  • Stimulated macrophages with various TLR ligands, including lipopolysaccharide (LPS).
  • Assessed macrophage survival rates and apoptotic rates.
  • Analyzed gene transcription, focusing on pro-apoptotic genes (Bak, Bax) and downstream signaling pathways (JNK).

Main Results:

  • ATF3-deficient macrophages exhibited reduced survival across multiple TLR ligand treatments.
  • Significantly increased apoptosis rates were observed in ATF3-deficient macrophages stimulated with LPS.
  • ATF3 functions downstream of JNK signaling following TLR engagement.
  • ATF3 represses the transcription of pro-apoptotic genes Bak and Bax.

Conclusions:

  • ATF3 is essential for TLR-mediated survival in macrophages, acting as a critical suppressor of apoptosis.
  • ATF3's role in regulating apoptosis is distinct from its previously known function in repressing pro-inflammatory cytokine transcription.
  • Targeting ATF3 could offer therapeutic strategies for inflammatory diseases by modulating macrophage apoptosis.

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