Classically activated macrophages use stable microtubules for matrix metalloproteinase-9 (MMP-9) secretion

Raed Hanania1, He Song Sun, Kewei Xu

  • 1Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.

Insights

Macrophages utilize microtubule (MT)-associated kinesin motors to traffic matrix metalloproteinase-9 (MMP-9) in vesicles. This mechanism is crucial for macrophage migration during inflammation.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Macrophages are key innate immune cells requiring migration to infected tissues.
  • Matrix metalloproteinases (MMPs), particularly MMP-9, are essential for macrophage transmigration by degrading extracellular matrix.
  • While MMP-9 secretion is known, its intracellular trafficking dynamics and mechanisms remain unclear.

Purpose of the Study:

  • To investigate the intracellular distribution and trafficking mechanisms of MMP-9 in activated macrophages.
  • To elucidate the role of microtubules and motor proteins in MMP-9 transport.

Main Methods:

  • Immunofluorescent imaging of RAW 264.7 macrophages.
  • Analysis of microtubule dynamics and association with MMP-9 vesicles.
  • Investigation of Rab3D and kinesin involvement in MMP-9 vesicle transport.

Main Results:

  • Intracellular MMP-9 was localized to Golgi-derived vesicles containing calreticulin and protein-disulfide isomerase.
  • MMP-9 vesicles were found to align along stable microtubules.
  • Rab3D-dependent kinesin association with MMP-9 vesicles was enhanced upon macrophage activation.
  • Kinesin 5B and 3B isoforms were implicated in the extracellular trafficking of MMP-9.

Conclusions:

  • Macrophage activation enhances the stabilization of microtubules, facilitating MMP-9 vesicle transport.
  • Kinesin motors, particularly isoforms 5B and 3B, are critical for the efficient extracellular trafficking of MMP-9 via microtubule-dependent pathways.
  • Understanding these trafficking mechanisms provides insights into macrophage migration during inflammatory responses.

Related Concept Videos

Role of Matrix Metalloproteases in Degradation of ECM01:23

Role of Matrix Metalloproteases in Degradation of ECM

Matrix metalloproteases (MMPs) are enzymes involved in the hydrolysis of proteins and glycoproteins of the extracellular matrix. MMPs are essential for the migration and proliferation of cells through the dense matrix network, throughout embryonic development, and throughout morphogenesis. The first MMP activity discovered was a collagenase in a tadpole's tail undergoing metamorphosis. The active collagen deposition and modifications lead to the morphogenesis of tadpoles into the adult body.
A...
Cancer Cell Migration through Invadopodia01:35

Cancer Cell Migration through Invadopodia

Invadosome is a broad category of cell surface structures with proteolytic activity that  degrades the extracellular matrix (ECM). Invadosomes are present in normal cell types, including macrophages, endothelial cells, and neurons, as well as tumor cells. Although the macrophage podosomes and tumor cell invadopodia are classified as invadosomes, they have different structures, molecular pathways, and functions. Podosomes are short structures that last for a few minutes. However, invadopodia can...
The Extracellular Matrix01:42

The Extracellular Matrix

Overview
The Extracellular Matrix01:29

The Extracellular Matrix

Overview
In order to maintain tissue organization, many animal cells are surrounded by structural molecules that make up the extracellular matrix (ECM). Together, the molecules in the ECM maintain the structural integrity of tissue as well as the remarkable specific properties of certain tissues.
Composition of the Extracellular Matrix
The extracellular matrix (ECM) is commonly composed of ground substance, a gel-like fluid, fibrous components, and many structurally and functionally diverse...