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Macrophages use apoptotic cell-derived methionine and DNMT3A during efferocytosis to promote tissue resolution

Patrick B Ampomah1,2, Bishuang Cai3, Santosh R Sukka4

  • 1Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. pbampomah1@gmail.com.

Nature Metabolism
|April 1, 2022
PubMed

Insights

Apoptotic cell clearance by macrophages involves methionine, which epigenetically represses Dusp4, promoting tissue resolution. This mechanism enhances pro-resolving mediators like PGE2 and TGF-β1, crucial for resolving inflammation.

Area of Science:

  • Immunology
  • Cell Biology
  • Epigenetics

Background:

  • Efferocytosis, the process by which macrophages clear apoptotic cells, is vital for tissue repair and homeostasis.
  • Dysfunctional efferocytosis is implicated in various diseases, highlighting the need to understand its resolution mechanisms.
  • The precise molecular pathways linking efferocytosis to pro-resolving mediator production remain incompletely elucidated.

Purpose of the Study:

  • To investigate the role of apoptotic cell-derived components in regulating efferocytosis-mediated tissue resolution.
  • To elucidate the epigenetic mechanisms controlling the expression of key pro-resolving mediators.
  • To identify therapeutic targets for diseases characterized by impaired resolution.

Main Methods:

  • Utilized in vitro and in vivo models of efferocytosis.
  • Investigated the epigenetic regulation of Dusp4 expression via DNA methylation.
  • Analyzed the signaling pathways involving ERK1/2, CD36, Ptgs2/COX2, PGE2, and TGF-β1.
  • Employed mouse models with bone marrow-specific deletion of DNMT3A.

Main Results:

  • Apoptotic cell-derived methionine epigenetically represses the ERK1/2 phosphatase Dusp4.
  • Efferocytosis induces Ptgs2/COX2, leading to PGE2 synthesis and subsequent TGF-β1 induction.
  • A negative feedback loop involving ERK1/2 and DUSP4 is overcome by efferocytosis-induced DUSP4 repression.
  • DNMT3A-mediated methylation of Dusp4 is essential for efferocytosis-induced resolution in vivo.
  • Deletion of DNMT3A in mice impairs resolution in models of sterile peritonitis, thymic injury, and atherosclerosis.

Conclusions:

  • Macrophage efferocytosis utilizes apoptotic cell-derived methionine to epigenetically regulate Dusp4, thereby controlling pro-resolving mediator synthesis.
  • This methionine-DUSP4-ERK-Ptgs2-PGE2-TGF-β1 axis is a critical pathway for efferocytosis-mediated tissue resolution.
  • Targeting this pathway offers potential therapeutic strategies for inflammatory and fibrotic diseases stemming from impaired resolution.

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