Symptomatic Carotid Atherosclerotic Plaques Are Associated With Increased Infiltration of Natural Killer (NK) Cells and Higher Serum Levels of NK Activating Receptor Ligands.

Irene Bonaccorsi,Claudia De Pasquale,Claudia Cantoni,Narayana Pipitò,Filippo Benedetto,Riccardo Cavaliere,Chiara Barillà,Guido Ferlazzo,Paolo Carrega,Daniela Oliveri,Domenico Spinelli

doi:10.3389/fimmu.2019.01503

Abstract

A wide array of immune cells, including lymphocytes, is known to be present and to play a pathogenetic role in atherosclerotic lesions. However, limited information is currently available regarding the presence of Natural Killer (NK) cell subsets within vessel plaque, and more in general, regarding their role in human atherosclerosis. We evaluated the distribution of NK cells in human carotid atherosclerotic plaques, dissecting asymptomatic and symptomatic patients (identified as affected by stroke, transient ischemic attack, or amaurosis fugax within 6 months) with the aim of shedding light on the putative contribution of NK cells to the pathogenic process that leads to plaque instability and subsequent clinical complications. We observed that carotid plaques were consistently infiltrated by NK cells and, among them, CD56brightperforinlow NK cells were abundantly present and displayed different markers of tissue residency (i.e., CD103 CD69 and CD49a). Interestingly, carotid atherosclerotic plaques of symptomatic patients showed a higher content of NK cells and an increased ratio between CD56brightperforinlow NK cells and their CD56dimperforinhigh counterpart. NK cells isolated from plaques of symptomatic patients were also stronger producers of IFN-γ. Analysis of the expression of NK activating receptor ligands (including MICA/B, ULBP-3, and B7-H6) in atherosclerotic carotid plaques revealed that they were abundantly expressed by a HLA-DR+CD11c+ myeloid cell population resident in the plaques. Remarkably, sera of symptomatic patients contained significant higher levels of soluble ligands for NK activating receptors. Our observations indicate that CD56bright NK cells accumulate within human atherosclerotic lesions and suggest a possible contribution of NK cells to the process determining plaque instability.

Highlights

Carotid atherosclerosisis is strongly associated with stroke and cerebrovascular disease
Previous studies demonstrated a functional role of Natural Killer (NK) cells in different experimental models of atherosclerosis, recent data derived from hypercolesterolemic mice failed to find a definite role for NK cells in atherosclerosis development
They demonstrated that NK cells might exacerbate atherosclerosis in case of activation induced by viral infections [17], an event frequently occurring throughout the whole life course

Summary

Introduction

Carotid atherosclerosisis is strongly associated with stroke and cerebrovascular disease. Some carotid atherosclerotic plaques (CAP) are stable and unlikely to produce symptoms, whereas others are unstable and may induce increased incidence of vascular complications. Symptomatic plaques generally reveal intima rupture, a thinner fibrous cap and a large necrotic core infiltrated by macrophages and lymphocytes. The complex molecular and cellular events underlying plaque destabilization are not completely elucidated and different immunological/inflammatory mechanisms are probably responsible for the clinical complications associated with unstable atherosclerotic plaques (AP). NK cells are large granular lymphocytes, divided in two main subsets: CD56dimCD16+cells are the majority in human peripheral blood (PB) (≥95%) [4], while CD56brightCD16− cells account for around 5% of NK cells in PB but represent the majority of NK cells in several peripheral tissues and in secondary lymphoid organs [5,6,7]. NK cells were mainly described in PB and, more recently, in lymphoid tissues [8,9,10], it is wellestablished that NK cells can be recruited at inflammatory sites [8, 10,11,12] and even enduringly reside in peripheral tissues at steady state [13,14,15]

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