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

Cristina Clemente, Cristina Rius, Laura Alonso-Herranz, Mara Martín-Alonso, Ángela Pollán, Emilio Camafeita, Fernando Martínez, Rubén A. Mota, Vanessa Núñez, Cristina Rodríguez, Motoharu Seiki, José Martínez-González, Vicente Andrés, Mercedes Ricote and Alicia G. Arroyo ()
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Cristina Clemente: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Cristina Rius: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Laura Alonso-Herranz: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Mara Martín-Alonso: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Ángela Pollán: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Emilio Camafeita: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Fernando Martínez: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Rubén A. Mota: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Vanessa Núñez: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Cristina Rodríguez: CIBER de Enfermedades Cardiovasculares (CIBERCV)
Motoharu Seiki: University of Tokyo
José Martínez-González: CIBER de Enfermedades Cardiovasculares (CIBERCV)
Vicente Andrés: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Mercedes Ricote: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
Alicia G. Arroyo: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Matrix metalloproteinases are involved in vascular remodeling. Little is known about their immune regulatory role in atherosclerosis. Here we show that mice deficient for MT4-MMP have increased adherence of macrophages to inflamed peritonea, and larger lipid deposits and macrophage burden in atherosclerotic plaques. We also demonstrate that MT4-MMP deficiency results in higher numbers of patrolling monocytes crawling and adhered to inflamed endothelia, and the accumulation of Mafb+ apoptosis inhibitor of macrophage (AIM)+ macrophages at incipient atherosclerotic lesions in mice. Functionally, MT4-MMP-null Mafb+AIM+ peritoneal macrophages express higher AIM and scavenger receptor CD36, are more resistant to apoptosis, and bind acLDL avidly, all of which contribute to atherosclerosis. CCR5 inhibition alleviates these effects by hindering the enhanced recruitment of MT4-MMP-null patrolling monocytes to early atherosclerotic lesions, thus blocking Mafb+AIM+ macrophage accumulation and atherosclerosis acceleration. Our results suggest that MT4-MMP targeting may constitute a novel strategy to boost patrolling monocyte activity in early inflammation.

Date: 2018
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DOI: 10.1038/s41467-018-03351-4

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