Regulation of T helper cell responses during antigen presentation by norepinephrine‐exposed endothelial cells

Abstract

Dermal blood vessels and regional lymph nodes are innervated by sympathetic nerves and, under stress, sympathetic nerves release norepinephrine (NE). Exposure of primary murine dermal microvascular endothelial cells (pDMECs) to NE followed by co-culture with Langerhans cells (LCs), responsive CD4 T-cells and antigen resulted in modulation of CD4 T-cell responses. NE-treatment of pDMECs induced increased production of interleukin (IL)-6 and IL-17A while down-regulating interferon (IFN)-γ and IL-22 release. This effect did not require contact between pDMECs and LCs or T-cells and depended upon pDMEC production of IL-6. The presence of NE-treated pDMECs increased the proportion of CD4 T-cells expressing intracellular IL-17A and increased IL-17A mRNA while decreasing the proportion of IFN-γ- or IL-22-expressing CD4 T-cells and mRNA levels for those cytokines. Retinoic acid receptor-related orphan receptor gamma (ROR-γt) mRNA was significantly increased in CD4 T-cells while T-box transcription factor (T-bet) mRNA was decreased. Intradermal administration of NE prior to hapten immunization at the injection site produced a similar bias in draining lymph node CD4 T-cells towards IL-17A and away from IFN-γ and IL-22 production. Under stress, release of NE may have significant regulatory effects on the outcome of antigen presentation through actions on ECs with enhancement of inflammatory skin disorders involving IL-17/T helper type 17 (Th17) cells.

α-Synuclein and Noradrenergic Modulation of Immune Cells in Parkinson’s Disease Pathogenesis

“…These cells are important actors in normal mucosal immunity, but they are also implicated in autoimmune pathology. Several studies have reported that treatment of CD4+ cells with NE promotes differentiation of Th17 cells and increases their activity (IL-17 production) while simultaneously inhibiting Th1 differentiation and activity (IFNγ production) ( Carvajal Gonczi et al, 2017 ; Xu et al, 2018 ). On the other hand, studies of Th17 cells from both mice and humans with Th17-mediated autoimmune diseases found that treating CD4+ T cells with NE inhibited the differentiation and activity of Th17 cells (IFNγ production was also still reduced) ( Boyko et al, 2016 ; Liu et al, 2018 ).…”

Rapid and sensitive surface‐enhanced resonance Raman spectroscopy detection for norepinephrine in biofluids

“…It is secreted by adrenal medulla and converted from tyrosine . As a kind of neurotransmitter, it plays an important role in living organism such as blood vessels and heart . Briefly, the main physiological function of NE is to stimulate receptor of blood vessels and make them contract.…”

The Endothelium: Global Integrator of Vascular-Immune Interactions

“…During this process, T cell membrane extensions protrude and form micro-contacts with antigen-presenting endothelial cells. It has been proposed that these T cell/EC microcontacts serve as sensory projections to facilitate antigen recognition by T cells [50][51][52][53].…”