Basement membrane damage by ROS- and JNK-mediated Mmp2 activation drives macrophage recruitment to overgrown tissue

Nat Commun. 2020 Jul 20;11(1):3631. doi: 10.1038/s41467-020-17399-8.

Abstract

Macrophages are a major immune cell type infiltrating tumors and promoting tumor growth and metastasis. To elucidate the mechanism of macrophage recruitment, we utilize an overgrowth tumor model ("undead" model) in larval Drosophila imaginal discs that are attached by numerous macrophages. Here we report that changes to the microenvironment of the overgrown tissue are important for recruiting macrophages. First, we describe a correlation between generation of reactive oxygen species (ROS) and damage of the basement membrane (BM) in all neoplastic, but not hyperplastic, models examined. ROS and the stress kinase JNK mediate the accumulation of matrix metalloproteinase 2 (Mmp2), damaging the BM, which recruits macrophages to the tissue. We propose a model where macrophage recruitment to and activation at overgrowing tissue is a multi-step process requiring ROS- and JNK-mediated Mmp2 upregulation and BM damage. These findings have implications for understanding the role of the tumor microenvironment for macrophage activation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Basement Membrane / metabolism
  • Basement Membrane / pathology*
  • Cell Proliferation
  • Disease Models, Animal
  • Drosophila / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / metabolism
  • Gene Expression
  • Imaginal Discs / immunology
  • Imaginal Discs / metabolism
  • Larva / metabolism
  • MAP Kinase Kinase 4 / metabolism
  • Macrophage Activation / physiology*
  • Macrophages / metabolism
  • Matrix Metalloproteinase 2* / genetics
  • Matrix Metalloproteinase 2* / metabolism
  • Reactive Oxygen Species / metabolism
  • Tumor Microenvironment / physiology*

Substances

  • Drosophila Proteins
  • Reactive Oxygen Species
  • MAP Kinase Kinase 4
  • Matrix Metalloproteinase 2