Neuronal plasticity and neuroregeneration in the skin — The role of inflammation

Abstract

The skin develops probably the densest and most complex innervation of all mammalian organs, consisting of sensory and autonomic nerves loaded with a plethora of neuropeptides and neurotransmitters. Skin innervation, as well as the expression patterns of neurotrophins and their receptors, is subject to dramatic changes during not only morphogenesis but also adult tissue remodeling under physiological or inflammatory conditions. Bilateral neuroimmune interactions are the basis of adaptive responses to tissue remodeling (such as hair cycling), psycho-emotional stress or skin inflammation. Dermatitis and hair loss may be exacerbated by stress-induced neurogenic inflammation. In addition, selected inflammatory skin diseases are associated with increased innervation. Finally, inflammatory cytokines influence the cutaneous expression of neurotrophins, as well as neurotrophin-induced neurite outgrowth following axotomy. Here, we review key studies on bilateral neuroimmune interactions in the skin under both healthy and disease conditions to provide a basis for future research on the role of inflammation in peripheral nerve regeneration.

Introduction

Traditionally, cutaneous innervation is described as divided into functional units. Broadly, there exists afferent sensory innervation receptive for touch, itch, pain etc., and efferent autonomic innervation, conducting glandular activity or smooth muscle contraction in blood vessels or arrector pili muscles (Allenby, 1970, Montagna, 1974, Munger and Ide, 1988, Paus et al., 1997, Tausk et al., 1993, Wallengren, 1997). Since the discovery of neurotransmitters and neuropeptides, we have learned that peripheral nerve fibers interact with their target tissues on multiple, complex levels. The number of known neuronal signaling molecules and their respective receptors in skin, as well as the list of their biological functions, continues to grow (Ansel et al., 1997, Botchkarev et al., 1999b, Paus et al., 1997, Peters et al., 2001, Scholzen et al., 1999). Peripheral innervation plays an important role in cutaneous immune processes (Asahina et al., 1995, Baluk, 1997, Holzer, 1998, Lotti et al., 1999, Pincelli et al., 1993, Weigent et al., 1990) as well as in wound healing (Fukai et al., 2005, Martin, 1997, Senapati et al., 1986, Stelnicki et al., 2000). Peripheral nerve fibers are also responsible for the maintenance of epithelial structures such as the epidermis, cornea, taste buds, and rete ridges (Abelli et al., 1993, Lundberg et al., 1979, Morohunfola et al., 1992, Munger, 1991). Vice versa, cutaneous innervation depends on target tissue integrity and is altered by inflammation or damage (Black, 2002, Groneberg et al., 2004, Steinhoff et al., 2003, Yasuda et al., 2003). Here, we will review the basic features of cutaneous innervation and neuronal plasticity during skin morphogenesis and adult skin remodeling, such as hair cycling and stress response. Furthermore, we review the literature on neuronal plasticity under inflammatory conditions. Finally, we outline important questions about neuroimmune interactions after skin nerve lesion, which require answers in order to enable systematic screening for pharmacological agents that support neuroregeneration in the skin.