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Area of Science:

  • Immunology
  • Cell Biology
  • Metabolic Regulation

Background:

  • Inflammation is a critical immune response to injury but can become excessive in disease.
  • The precise molecular mechanisms governing inflammatory responses remain incompletely understood.
  • Cell surface glycoprotein CD44 is involved in cell phenotype regulation during immunity and cancer.

Purpose of the Study:

  • To elucidate the molecular basis of inflammatory responses.
  • To investigate the role of copper in cellular inflammation.
  • To develop a therapeutic strategy targeting inflammatory pathways.

Main Methods:

  • Investigated the role of CD44 in metal uptake, specifically copper.
  • Identified reactive copper(II) in mitochondria of inflammatory macrophages.
  • Analyzed the catalysis of NAD(H) redox cycling and its link to hydrogen peroxide.
  • Utilized supformin (LCC-12), a metformin dimer, to target mitochondrial copper.
  • Assessed metabolic and epigenetic reprogramming in macrophages.
  • Evaluated LCC-12 efficacy in mouse models of bacterial and viral infections.

Main Results:

  • CD44 mediates the uptake of metals, including copper.
  • Mitochondrial copper(II) catalyzes NAD(H) redox cycling, promoting inflammatory metabolic and epigenetic states.
  • Targeting mitochondrial copper with LCC-12 reduces the NAD(H) pool, opposing macrophage activation.
  • LCC-12 demonstrates efficacy in reducing inflammation in vivo.

Conclusions:

  • Copper is a key regulator of cell plasticity and inflammatory responses.
  • Targeting mitochondrial copper offers a novel therapeutic approach for inflammatory diseases.
  • Metabolic reprogramming and epigenetic control are viable strategies for managing inflammation.