Papel de la proteasa MT4 MMP como modulador de los monocitos patrulleros en el contexto inflamatorio

Abstract

Patrolling monocytes are a population of circulating leukocytes in the blood responsible for tracking the endothelium of the vessels, detecting cellular damage and capturing harmful particles both in homeostasis conditions and during inflammatory processes. In our work we have characterized the role of the MT4-MMP matrix protease (MMP17) in patrollling monocytes and macrophages in the context of inflammation. After confirming the expression of MT4-MMP in macrophages during sterile peritonitis and atherosclerosis, we observed that the absence of MT4-MMP involved an accumulation of macrophages both in the inflamed peritoneal membrane and in the atheroma plaque and that these macrophages express the MafB transcription factor and its target gene AIM/CD5L.We also show that macrophages lacking MT4-MMP express higher levels of the receptor CD36 and are more active in capturing modified lipids, resulting in an acceleration of atherosclerosis. The absence of MT4-MMP also increases the number of patrolling monocytes attached to the incipient atheroma plaque and blocking this recruitment prevents the accumulation of MafB+AIM/CD5L+macrophages, lipid deposits and acceleration of atherosclerosis. Therefore MT4-MMP seems to regulate primarily patrolling monocyte early adhesion and recruitment during inflammation. In this sense, we observe that in the absence of MT4-MMP there is an accumulation of the αMβ2 integrin in the membrane of the patrolling monocytes and the peritoneal macrophages. By in silico and in vitro digestion tests we determine that MT4-MMP is able to process the αM chain of the αMβ2 integrin, thus modulating its levels in the monocyte and macrophage membrane. Finally, through intravital microscopy we demonstrate in vivo that the absence of MT4-MMP increases the number of patrolling monocytes able to crawl on the inflamed endothelium in a manner dependent on the integrin αMβ2. In summary, this work identifies MT4-MMP as a new regulator of the function of patrolling monocytes through the processing of integrin αM. As a consequence, the absence of MT4-MMP increases the number of patrolling monocytes that crawl on the inflamed endothelium which could be beneficial in pathologies such as Alzheimer's disease, lung metastasis or infections.