Nerve growth factor receptor expression marks activated human perivascular adventitial fibroblasts in distinct perturbed states

Abstract

Abstract Vascular alterations are common in human autoimmune skin diseases, including systemic sclerosis and discoid lupus. Much is known about endothelial cell, pericyte and vascular smooth muscle cell activation. In contrast, the adventitial layer of the vascular unit is less well explored. This compartment serves as a reservoir for leukocytes and mesenchymal stem cells, and appears to play important sentinel and remodeling roles. We recently demonstrated that the compartment, as well as the perivascular adventitial fibroblasts, expand in the skin of systemic sclerosis, discoid lupus, and dermatitis patients. Vascular cell adhesion molecule-1 (VCAM) display marked activated adventitial fibroblasts in discoid lupus and dermatitis, and correlated with perivascular T cell infiltration. Here we demonstrate elevated expression of Nerve growth factor receptor (NGFR) by perivascular adventitial fibroblasts in the skin of systemic sclerosis patients but not control subjects. Adventitial NGFR expression occurred without elevated VCAM indicating a distinct activation state. Conversion to the NGFR+ state was also observed in the absence of large, perivascular leukocyte infiltrates. In systemic sclerosis, NGFR was more common than VCAM on perivascular adventitial fibroblasts. Conversely, in discoid lupus lesions, VCAM was more common than NGFR on adventitial fibroblasts suggesting two distinct activation programs. Similar adventitial NGFR staining was seen in both pathological (e.g. hypertrophic and keloid) and normal reparative skin wounds. Our data indicate that elevated NGFR expression can identify an activated perivascular adventitial fibroblast in disease.