Stress exposure modulates peptidergic innervation and degranulates mast cells in murine skin

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Abstract

Stress is said to induce itchiness of the skin, exacerbate inflammatory skin diseases, and inhibit wound healing. Neuropeptides such as substance P (SP) may play a role in these processes. Recently, we were able to show that both stress or SP are associated with neurogenic inflammation and increased apoptosis in the murine hair follicle. Moreover, peptidergic cutaneous innervation is subject to lifelong plasticity due to its association with the cyclic growth of hair follicles. However, peripheral neuronal plasticity has never been reported in altered interactions between the nervous and immune systems under perceived stress. Here, we show for the first time plasticity of the cutaneous peptidergic innervation in response to stress. After exposure to sonic stress, the number of SP+ nerve fibers in the back skin of C57BL/6 mice with their hair follicles in the resting phase of the hair cycle (telogen—low numbers of nerve fibers) increased significantly. Such nerve fibers contacted mast cells more frequently. At the same time, the percentage of degranulated mast cells increased significantly associated with a rise in apoptotic cells in the skin. Increased numbers of peptidergic nerve fibers correlated with increased numbers of growth-associated protein 43 (Gap-43)+ nerve fibers, which is a marker for growing nerves. Thus, neuronal plasticity and increased neuro-immune interaction occur under stress and may alter inflammatory skin diseases and trophic functions in the skin where neurogenic inflammation plays a part.

Introduction

Stress is said to induce itchiness of the skin, exacerbate inflammatory skin diseases, and worsen wound healing (Kimyai-Asadi and Usman, 2001, Panconesi and Hautmann, 1996, Picardi and Abeni, 2001). Altered disease pathology is mostly attributed to central activation of the hypothalamus–pituitary–adrenal axis (HPA axis) or the sympathetic nervous system (Black, 2002, Buske-Kirschbaum et al., 2001, Slominski and Wortsman, 2000) and thereby systemic changes in the immune response. However, itchiness, inflammatory skin diseases, and wound healing have also been associated with altered innervation of peripheral tissues and thereby altered neuro-immune interaction. Moreover, there is ample evidence that stress can induce neurogenic inflammation in the skin by releasing the neuropeptide substance P (SP) and other neuromediators from peripheral nerve endings, resulting in subsequent mast cell degranulation (Arck et al., 2001, Arck et al., 2003, Singh et al., 1999).

Neuronal plasticity, which is defined as continuous adaptive growth, reorganization, and modification of nerve–nerve and nerve–tissue interaction, was traditionally thought to occur exclusively upon injury (cf. Paus et al., 1997). Recent research suggests plasticity in the adult peripheral innervation in healthy human and murine skin by the presence of growth-associated protein 43 (Gap-43), a marker for neuronal plasticity (Botchkarev et al., 1997a, Botchkarev et al., 1997b, Botchkarev et al., 1999, Fantini and Johansson, 1992).

Hairy skin contains numerous epithelial, vascular, muscular, and glandular components that receive sensory innervation and express neuropeptide receptors or even produce neuropeptides themselves (Paus et al., 1997, Steinhoff et al., 2003). We were recently able to show that both stress and SP are associated with mast cell degranulation, increased cutaneous neurogenic inflammation, and apoptosis in the hair follicle, thereby inducing the growing hair follicle to regress prematurely (Arck et al., 2003). Altered cutaneous innervation under stress has also been shown in psoriasis (Harvima et al., 1993). Thus, increasing evidence emerges for a close relationship between cutaneous innervation, the skin immune system and the cutaneous neuroendocrine system in adapting to a perceived threat (Arck et al., 2001, Paus et al., 1997, Steinhoff et al., 2003), and the peripheral nervous system is involved in a psychoneuroimmune brain–skin axis (Arck et al., 2001). However, stress exposure-induced plasticity of the peripheral neural networks and its implications for neurogenic inflammation and associated disease have never been reported.

Here, we address the intriguing question of whether and how stress modulates neurogenic inflammation via altered neuro-immune interaction and whether this is a result of peripheral neuronal plasticity. To this end, we analyzed SP-immunoreactive (SP+) nerve fibers, SP+ nerve fiber–mast cell contacts, mast cell degranulation, and apoptotic cells to assess neurogenic inflammation and subsequent tissue damage in the dermis of stressed mice. We also analyzed the number of Gap-43-immunoreactive nerve fibers, as a marker for growing nerve fibers to assess plasticity of the peripheral nervous system under stress (Benowitz and Routtenberg, 1997, Fishman, 1996). We expect that this approach will lead to a better understanding of stress maladaptation in health and disease and facilitate the development of new therapeutic approaches in the management of stress-sensitive diseases such as telogen effluvium, atopic dermatitis, psoriasis, or wound healing.

Section snippets

Mice and skin harvesting

Six- to nine-week-old, syngenic, female C57BL/6 mice were purchased from Charles River (Sulzfeld, Germany). Mice at this age show the most reliable and profound stress-response, as identified in various experimental settings to investigate inflammatory diseases (Arck et al., 2001, Arck et al., 2003, Blois et al., 2004, Clark et al., 1993, Joachim et al., 2003, Qiu et al., 1999). Also, mice show synchronized hair growth in their back skin during early life, i.e., all back skin hair follicles are

SP-immunoreactive nerve fiber numbers increase upon stress exposure

C57BL/6 telogen mice show a significant increase in the number of SP+ nerve fibers over non-stressed mice (Fig. 1, Fig. 2) 24 and 48 h after sonic stress exposure. The strongest increase over control levels was observed after 24 h and the number of SP+ nerve fibers appeared to mildly decline between 24 and 48 h after termination of stress exposure (Fig. 2). Most of these fibers were single nerve fibers that terminated freely in the dermis or innervated dermal blood vessels. Epidermal nerve fibers

Discussion

Here, we show for the first time that perceived stress potently and effectively induces neuronal plasticity and alters the neuro-immune-biology of the skin in telogen mice. SP+ nerve fiber numbers are increased and SP+ nerve fibers are found close to degranulating mast cells of stressed mice, indicating plasticity in the peptidergic innervation and neuro-immune communication in skin. At the same time, tissue is damaged as evidenced by the increased number of apoptotic cells in skin. Parallel to

Acknowledgments

This study was supported in part by grants from the Humboldt-University of Berlin, Germany to Eva Peters (AF 2004-159) and the German Research Foundation to E.M.J.P. (DFG Pe 890/1-3 and 3-1) and P.C.A. (AR 232/14-1). Many thanks to Christa Josties for technical assistance and Kimberly Rosegger for editing the manuscript.

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