Stress exposure modulates peptidergic innervation and degranulates mast cells in murine skin
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.
References (53)
- et al.
Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollikular inflammatory events via neuropeptide substance P-dependent pathways
Am. J. Pathol.
(2003) - et al.
GAP-43: an intrinsic determinant of neuronal development and plasticity
Trends Neurosci.
(1997) Stress and the inflammatory response: a review of neurogenic inflammation
Brain Behav. Immun.
(2002)- et al.
Hair cycle-dependent changes in adrenergic skin innervation, and hair growth modulation by adrenergic drugs
J. Invest. Dermatol.
(1999) - et al.
Expression of growth-associated protein 43 and nerve growth factor receptor in human skin: a comparative immunohistochemical investigation
J. Invest. Dermatol.
(1992) - et al.
Neural regulation of endothelial cell-mediated inflammation
J. Invest. Dermatol. Symp. Proc.
(2000) - et al.
A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages
J. Invest. Dermatol.
(2001) - et al.
BDNF as an anterophin; a novel neurotrophic relationship between brain neurons
Trends Neurosci.
(2001) - et al.
Neural mechanisms of hair growth control
J. Invest. Dermatol. Symp. Proc.
(1997) - et al.
Hair-cycle-associated remodeling of the peptidergic innervation of murine skin, and hair growth modulation by neuropeptides
J. Invest. Dermatol.
(2001)
Immobilization stress rapidly modulates BDNF mRNA expression in the hypothalamus of adult male rats
Neuroscience
Depletion of neuropeptides during wound healing in rat skin
Neurosci. Lett.
Acute immobilization stress triggers skin mast cell degranulation via corticotropin releasing hormone, neurotensin, and substance P: a link to neurogenic skin disorders
Brain Behav. Immun.
Increased number of immunoreactive nerve fibers in atopic dermatitis
J. Allergy Clin. Immunol.
Indications for a ‘brain-hair follicle axis (BHA)’: inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P
FASEB J.
Stress-induced murine abortion associated with substance P-dependent alteration in cytokines in maternal uterine decidua
Biol. Reprod.
Depletion of CD8+ cells abolishes the pregnancy protective effect of progesterone substitution with dydrogesterone in mice by altering the TH1/TH2 cytokine profile
J. Immunol.
Hair cycle-dependent plasticity of skin and hair follicle innervation in normal murine skin
J. Comp. Neurol.
A simple immunofluorescence technique for simultaneous visualization of mast cells and nerve fibers reveals selectivity and hair cycle-dependent changes in mast cell–nerve fiber contacts in murine skin
Arch. Dermatol. Res.
Psychobiological aspects of atopic dermatitis: an overview
Psychother. Psychosom.
Endogenous substance P inhibits the expression of corticotropin-releasing hormone during a chronic inflammatory stress
Life Sci.
Stress-triggered abortion in mice prevented by alloimmunization
Am. J. Reprod. Immunol.
GAP-43: putting constraints on neuronal plasticity
Perspect. Dev. Neurobiol.
Skin nerve fibres and their contacts with mast cells in patients with palmoplantar pustulosis
Arch. Dermatol. Res.
Association of cutaneous mast cells and sensory nerves with psychic stress in psoriasis
Psychother. Psychosom.
Role of T cells in atopic dermatitis. New aspects on the dynamics of cytokine production and the contribution of bacterial superantigens
Int. Arch. Allergy Immunol.
Cited by (111)
Peripheral inflammation-induced changes in songbird brain gene expression: 3’ mRNA transcriptomic approach
2024, Developmental and Comparative ImmunologyThe impact of perceived stress on the hair follicle: Towards solving a psychoneuroendocrine and neuroimmunological puzzle
2022, Frontiers in NeuroendocrinologyTo stress or not to stress: Brain-behavior-immune interaction may weaken or promote the immune response to SARS-CoV-2
2021, Neurobiology of StressCitation Excerpt :Correspondingly, acute infection shares many features with an acute response to psychosocial stress, both of which increase the levels of IL-1β, IL-6 and TNFα (Marsland et al., 2017); cytokines, which are also known to boost the response to vaccine in short-term stress paradigms such as single restraint-stress exposure in mice (Dhabhar and Viswanathan, 2005). This acute innate and TH1 immune response interacts positively with an activated adrenergic stress axis and rapid while transient HPA activation as well as with neuropeptidergic and neurotrophinergic stress mediators (Dhabhar, 2018; Kolmus et al., 2014; Peters et al., 2005; Taylor et al., 2012). Endogenously produced (nor)adrenaline and cortisol for example initially promote host defense mechanisms as they transiently increase IL-1β, TNFα and NK-cell activity.
Enduring neuroimmunological consequences of developmental experiences: From vulnerability to resilience
2020, Molecular and Cellular Neuroscience