233 Langerhans cells as targets of neuroimmune Communication in the Epidermal Compartment of Human Skin

Abstract

The immune system is strongly linked to the nervous system, to the point that in many diseases they cannot be discussed as separate entities. Specifically, inflammatory skin diseases such as atopic dermatitis and psoriasis have been reported to be intensified by stress, and, interestingly the skin lesions in these diseases sometimes resolve after nerve injury. The putative cause underlying this empirical observation is that sensory nerves secrete neuropeptides (NPs) and other mediators that are important members of neuro-immune communication. Inside the epidermis, the only dedicated resident immune cells under steady-state are the antigen-presenting cells called Langerhans cells (LCs). LCs have been shown to be anatomically associated with neurons that produce Calcitonin Gene-Related Peptide (CGRP), supporting the hypothesis that NPs possibly play a role in cutaneous inflammation. Previous reports have shown that CGRP reduces LC antigen-presentation to a Th1 clone while simultaneously, enhancing antigen-presentation for Th2 clones in mice, but little is known in humans. As a first, exploratory step we utilized RNA sequencing from monocyte-derived LCs samples from five donors and we detected the expression of neuropeptide receptor genes. We found high expression of CGRP receptor and its coreceptor RAMP1 and also one of the neurotensin receptors (SORT1, also known as NTR3) and the Brain Natriuretic peptide receptor NPR1, and validated these with RT-qPCR. We also determined the effect of all three neuropeptides on the differentiation of monocyte-derived LCs with flow cytometry and found that NPR1 activation significantly increased the differentiation of LCs, while the others had no effect. Interestingly, BNP had only minimal effect on the T cell stimulatory capability of LCs, or on their cytokine (IL-6, IL-8, IL-10 and IL-12) production. These data suggest that neuroimmune communication might be an important prerequisite of LC differentiation.