Neural Regulation of Endothelial Cell-Mediated Inflammation

Abstract

There is increasing evidence that the cutaneous neurosensory system can directly modulate inflammatory responses in the skin by the release of neuropeptides such as substance P (SP). Dermal microvascular endothelial cell (DMEC) cellular adhesion molecule (CAM) expression plays a key role in directing leukocyte trafficking during cutaneous inflammatory responses. In recent studies, our laboratory examined the direct effect of SP on DMEC CAM expression and function in vitro and in vivo. Our studies indicate that DMEC express high affinity functional receptors for SP. After exposure to SP, DMEC expressed significant levels of both intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), which was accompanied by increased binding to leukocytes expressing the appropriate integrin counter receptors for these CAM. We then determined the in vivo effect of released neuropeptides on DMEC CAM expression. Our results indicate that the topical cutaneous application of the neuropeptide-releasing agent capsaicin resulted in increased ICAM-1 and VCAM-1 immunostaining of microvascular cells in the skin of human volunteers. Little is known regarding the cellular regulatory events by which SP modulates DMEC CAM expression. Our studies indicate that SP-induced cellular Ca+2 signals led to the activation of the NF-kappaB pathway, resulting in nuclear translocation of p65/p50 heterodimers that bind to high-affinity tandem kappaB sites on the VCAM-1 promoter, whereas SP activation induced NF-AT activation and ICAM-1 DNA binding. Thus, these studies further support the role of the cutaneous neurologic system in modulating inflammatory processes in the skin.

Protease-Activated Receptor-2 Activation Induces Acute Lung Inflammation by Neuropeptide-Dependent Mechanisms

“…Epithelial and endothelial cells are both candidate targets of neurokinins released upon activation of PAR2 in the lung (17,41,42). Also, the alveolar macrophage is a potential effector cell.…”

The Role of Neuromediators and Innervation in Cutaneous Wound Healing

“…SP stimulates vasodilatation and micro-vascular permeability through increasing nitric oxide release and through direct effects on endothelial cells (32). SP up-regulates expression of adhesion molecules on endothelial cells, monocyte chemotaxis and inflammatory cell activity (33)(34)(35). SP also modulates the synthesis and release of pro-inflammatory cytokines such as interleukins, transforming growth factor-α (TGF-α) and tumour necrosis factor-α; key components during the inflammatory phase of wound healing (36).…”

Role of neurokinin-1 receptor in the initiation and maintenance of skin chronic inflammatory diseases

“…These in turn stimulate mast cell degranulation with release of histamine and serotonin, which trigger the subsequent vascular response including vasodilatation (erythema) and increased permeability (edema) [65]. Simultaneously, signaling via NK1R by SP up-regulates the expression of vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule-1 (ICAM) by blood endothelial cells resulting in extravasation of inflammatory cells with skin-homing capacities [66].…”