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Abstract
The pathophysiology of systemic sclerosis (SSc) involves early endothelial and immune activation, both preceding the onset of fibrosis. We previously identified soluble fractalkine and circulating endothelial microparticles (EMPs) as biomarkers of endothelial inflammatory activation in SSc. Fractalkine plays a dual role as a membrane-bound adhesion molecule expressed in inflamed endothelial cells (ECs) and as a chemokine involved in the recruitment, transmigration, and cytotoxic activation of immune cells that express CX3CR1, the receptor of fractalkine, namely CD8 and γδ T cells and natural killer (NK) cells. We aimed to quantify circulating cytotoxic immune cells and their expression of CX3CR1. We further investigated the expression profile of NK cells chemokine receptors and activation markers and the potential of NK cells to induce EC activation in SSc. We performed a monocentric study (NCT 02636127) enrolling 15 SSc patients [15 females, median age of 55 years (39–63), 11 limited cutaneous form and 4 diffuse] and 15 healthy controls. Serum fractalkine levels were significantly increased in SSc patients. Circulating CD8 T cells numbers were decreased in SSc patients with no difference in their CX3CR1 expression. Circulating γδ T cells and NK cells numbers were preserved. CX3CR1 expression in CD8 and γδ T cells did not differ between SSc patients and controls. The percentage and level of CX3CR1 expression in NK cells were significantly lowered in SSc patients. Percentages of CXCR4, NKG2D, CD69-expressing NK cells, and their expression levels were decreased in NK cells. Conversely, CD16 level expression and percentages of CD16+ NK cells were preserved. The exposure of human microvascular dermic EC line (HMVEC-d) to peripheral blood mononuclear cells resulted in similar NK cells degranulation activity in SSc patients and controls. We further showed that NK cells purified from the blood of SSc patients induced enhanced release of EMPs than NK cells from controls. This study evidenced a peculiar NK cells phenotype in SSc characterized by decreased chemokine and activation receptors expression, that might reflect NK cells involvement in the pathogenic process. It also highlighted the role of NK cells as a potent mechanism inducing endothelial activation through enhanced EMPs release.
Highlights
Systemic sclerosis (SSc) is a complex systemic autoimmune disease characterized by small vessel vasculopathy and multi-organ fibrosis with a lung involvement, highly related to morbidity and mortality [1]
We first aimed to determine whether absolute numbers of circulating cytotoxic immune cells, namely CD8 T cells, Natural killer (NK) cells, or γδ T cells, were affected in SSc patients
The percentage of CX3CR1+ NK cells was significantly lower in SSc patients [87.63% (74.54–98.28)] than in healthy controls [99.03% (96.95–99.21), p = 0.0023] (Figure 4A)
Summary
Systemic sclerosis (SSc) is a complex systemic autoimmune disease characterized by small vessel vasculopathy and multi-organ fibrosis with a lung involvement, highly related to morbidity and mortality [1]. The damage of endothelial cells (ECs) is believed to be an early event in the natural history of SSc and may involve environmental, genetic factors, and excessive innate immune responses [2]. The disruption of vascular integrity and the subsequent acquisition of an activated endothelial phenotype favor the local recruitment of activated leukocytes and sustain the development of the vasculopathy and tissue fibrosis. Activated immune cells release soluble inflammatory cytokines and pro-fibrotic growth factors that further activate SSc fibroblasts. The cross talk between activated ECs, fibroblasts, and immune effectors is a major mechanism underlying the pathogenesis and clinical progression of the disease [3,4,5,6]. A better understanding of the quantitative and functional alterations of immune cells is needed in order to shed light on the still unclear pathogenic processes
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