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Systematic perturbation screens identify regulators of inflammatory macrophage states and a role for TNF mRNA m6A

Simone M Haag1, Shiqi Xie1, Celine Eidenschenk1

  • 1Genentech Inc., South San Francisco, CA, USA.

Nature Genetics
|October 24, 2024
PubMed

Insights

Researchers uncovered how macrophages develop inflammatory states during chronic inflammation. They found that blocking N6-methyladenosine (m6A) modification of TNF transcripts enhances mRNA stability and tumor necrosis factor (TNF) production, impacting innate immunity.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genomics

Background:

  • Macrophages are crucial for tissue homeostasis and exhibit plasticity.
  • Chronic inflammation involves sustained inflammatory macrophage states that contribute to disease.
  • Regulatory mechanisms driving these inflammatory states are poorly understood.

Purpose of the Study:

  • To systematically identify regulatory circuits controlling inflammatory states in macrophages.
  • To uncover mechanisms underlying the generation of sustained inflammatory macrophage phenotypes.

Main Methods:

  • Genome-wide phenotypic screening in primary murine macrophages.
  • Transcriptional and cytokine profiling of genetic perturbations in primary human macrophages.
  • Functional genomics approach combining in vivo and in vitro studies.

Main Results:

  • Identified regulators for five distinct macrophage inflammatory states.
  • Loss of N6-methyladenosine (m6A) writer components abolished m6A modification of TNF transcripts.
  • Enhanced TNF mRNA stability and production were observed upon loss of m6A writers.

Conclusions:

  • Phenotypic characterization reveals regulatory circuits of distinct macrophage inflammatory states.
  • Post-transcriptional control of TNF mRNA stability is a key mechanism in innate immunity.
  • m6A modification regulates TNF production and inflammatory responses.

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