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MT4-MMP deficiency increases patrolling monocyte recruitment to early lesions and accelerates atherosclerosis

Cristina Clemente1, Cristina Rius2,3, Laura Alonso-Herranz4

  • 1Matrix Metalloproteinases in Angiogenesis and Inflammation Group, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain.

Nature Communications
|March 4, 2018
PubMed

Insights

Mice lacking MT4-MMP show increased macrophage accumulation and atherosclerosis. Targeting MT4-MMP may enhance patrolling monocyte activity to combat early inflammation and cardiovascular disease.

Area of Science:

  • Immunology and Cardiovascular Research
  • Molecular Biology and Disease Mechanisms

Background:

  • Matrix metalloproteinases (MMPs) are implicated in vascular remodeling.
  • The immune regulatory functions of MMPs, particularly in atherosclerosis, remain largely unexplored.
  • Understanding MMP roles is crucial for novel therapeutic strategies against atherosclerosis.

Purpose of the Study:

  • To investigate the immune regulatory role of MT4-MMP in atherosclerosis.
  • To elucidate the mechanisms by which MT4-MMP influences macrophage behavior and recruitment.
  • To explore potential therapeutic targets for early-stage inflammatory processes in atherosclerosis.

Main Methods:

  • Utilized MT4-MMP deficient mice models to study atherosclerosis development.
  • Analyzed macrophage adherence, lipid deposition, and monocyte recruitment in inflamed tissues and atherosclerotic plaques.
  • Investigated the expression of AIM and CD36 in macrophages and assessed their apoptosis resistance and acLDL binding.
  • Examined the effect of CCR5 inhibition on monocyte recruitment and lesion progression.

Main Results:

  • MT4-MMP deficiency led to increased macrophage adherence, larger lipid deposits, and higher macrophage burden in atherosclerotic plaques.
  • Absence of MT4-MMP resulted in elevated patrolling monocyte activity and accumulation of Mafb+ apoptosis inhibitor of macrophage (AIM)+ macrophages.
  • MT4-MMP-null macrophages exhibited increased AIM, CD36 expression, apoptosis resistance, and avid acLDL binding, promoting atherosclerosis.
  • CCR5 inhibition mitigated these effects by reducing monocyte recruitment and subsequent macrophage accumulation, thereby slowing atherosclerosis acceleration.

Conclusions:

  • MT4-MMP plays a significant role in regulating macrophage behavior and monocyte recruitment in atherosclerosis.
  • MT4-MMP deficiency exacerbates atherosclerosis by promoting pro-atherogenic macrophage phenotypes and accumulation.
  • Targeting MT4-MMP could be a novel strategy to modulate patrolling monocyte activity in early inflammatory conditions, potentially preventing atherosclerosis.

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