Download Neural control of skin water content: The sebaceous gland, a

Curr Neurobiol 2016; 7 (3): 74-76
ISSN 0975-9042
Neural control of skin water content: The sebaceous gland, a neglected target.
Pierre A Guertin
University Laval and CHU de Québec, Canada.
Abstract
Normally supple and moist, the skin is the largest organ and outermost structure of
the body. It is composed of separate but interconnected layers, working as a whole but
controlled distinctively by numerous modulatory signals arising from several areas of
the central, peripheral and autonomous nervous systems (CNS, PNS, ANS, respectively).
Almost all functions mediated by that organ depend significantly upon water content levels
of its constitutive layers. There is increasing evidence suggesting that a pivotal mechanism
involved in water content modulation is the sebaceous gland. Its dysfunction has also
been associated with debilitating dry skin problems such as xerosis, atopic dermatitis,
psoriasis and rosacea. Generally, sebum secretion levels are considered to be dependent
upon sex hormone (e.g. testosterone, DHEA) release – attributed to neuroendocrine actions
(hypothalamus-pituitary-gonadal axis-control) on various organs. However, clear evidence
indicate that specific neuropeptides and peripheral nerves can also participate significantly
to the regulation of sebum secretion and, hence, to skin moisture and functions. This editorial
aims at summarizing some of the main findings in neural control mechanisms of normal
skin functions – specifically those associated with sebaceous gland activity.
Accepted November 15, 2016
Functional Anatomy of the Skin
The skin is the largest organ (~2 m2) of our body and the first
line of defense from external factors. It prevents excessive
water content losses and, as such, serves as a lipid-rich
structure involved in regulating body temperature. The
mammalian skin is composed of four layers – namely the
epidermis, basement membrane, dermis and subcutaneous
or hypodermis. None of the epidermis sublayers (stratum
corneum or SC, granolosum or SG, spinosum, basal) contains
blood vessels per se although the deepest layers are ‘nourished’
so to speak by diffusion from blood capillaries extending to
the upper layers of the dermis [1-3]. The dermis provides
strength and elasticity to the skin through an extracellular
matrix composed of collagen fibrils, microfibrils and elastic
fibers, embedded in hyaluronan and proteoglycans [4]. It
harbors blood vessels, mechanoreceptors, thermoreceptors
and nociceptors that provide the sense of touch, pressure and
heat as well as biological fluids released from sudoriferous
and sebaceous glands [5,6].
Generally-Shared Knowledge
Control of Skin Functions
about
Neural
The sensory roles attributed to skin functions are rather
74
well-described in textbooks. Cutaneous nerves and sensory
elements of the peripheral nervous system (PNS) respond
to stimuli from the circulation and to emotions (“internal
trigger factors”) as well as from peripheral receptors
(i.e., mechanoreceptors, nociceptors, thermoreceptors,
chemoreceptors) by sending directly or indirectly to the
CNS, inputs involved in sensations (hot/cold, pressure/
touch, pain, vibration, chemicals, etc.), vasocontraction,
vasodilatation, body temperature regulation, barrier
function, secretion, growth, differentiation, cell nutrition,
nerve growth, inflammatory and immune responses,
apoptosis, proliferation, and wound healing [1].
Water Content Levels and Skin Health
The inner milieu of our body consists of about 70% water
(gender- and age-based differences ranging from 55-75%)
whereas surrounding ambient air carries less than 1% water
[2]. Consequently, skin water content tends to decrease
more or less rapidly through sweating and evaporation and
without normal mechanisms for steady replenishment of
skin water content level, xerosis and other skin problems,
for which skin dryness plays a role, are bound to be
experienced. Two main mechanisms affect water content
at the cellular level – 1) water transport from inner
Curr Neurobiol 2016 Volume 7 Issue 3
Neural control of skin water content: The sebaceous gland, a neglected target.
layers towards the epidermis and, 2) water transport and
evaporation from epidermal layers towards the exterior.
Water Transport from Inner Layers to the
Epidermis
Skin hydration levels are regulated by water transport
from inner layers, including from blood vessels, that seek
bringing in water towards the dermis and, hence, to the
epidermis. In other words, water travels from the deeper
skin layers towards outmost skin layers to hydrate cells of
the SC – where it is eventually being lost to evaporation.
Increasing skin water content is thus achievable through
enhanced activity of Aquaporin channels, supported by
water-binding molecules such as glycerol, expressed
on vascular endothelial cells where it facilitates water
exchange and transport between blood and dermis
[7]. In other words, body water levels as well as blood
volumes, circulating flow levels and regional distribution
can significantly affect skin water content levels [8].
Indirectly, neural control of water transport may be
achieved by neuroendocrine responses (hypothalamicpituitary-adrenal axis) through control of vasodilation
and vasoconstriction. Arteriovenous anastomoses (AVAs)
have been found to play a key role in cutaneous blood flow
regulation – e.g. dilating AVAs for increased cutaneous
vascular volume enabling more blood to enter deep skin
layers [9]. More directly, other structures of the CNS can
also alter vasodilation mechanisms - the medullary raphe
nucleus, the rostral ventrolateral medulla oblongata, the
preoptic area, the dorsomedial hypothalamus, the ventral
tegmental area and the periaqueductal gray matter area
[10-13].
Water Transport and Evaporation from
Epidermal Layers to the Exterior
Although, water content levels vary accordingly to skin
layer (70% in SG but 15-30% in SC), reducing water
transport towards the outmost layers and increasing waterbinding capabilities while reducing evaporation constitute
another main mechanism of skin water content regulation
[14]. Large reservoirs of water reside in the dermis where
most water-binding molecules are expressed - the collagen
fibers, the interstitial space glycosaminoglycans and the
proteoglycans. A novel role of sebaceous glands in skin
water content has recently been unraveled. The normal
function of sebaceous glands is to produce and secrete
sebum, a group of complex oils including triglycerides
and fatty acid breakdown products, wax esters, squalene,
cholesterol esters and cholesterol [15]. Sebum lubricates
the skin to protect against friction and to make it more
impervious to moisture. Furthermore, the sebaceous gland
transports antioxidants in and on the skin and exhibits
a natural light protective activity. It also possesses an
innate antibacterial activity and has a pro- and antiinflammatory function. It can regulate the activity of
xenobiotics and is actively involved in the wound healing
process. Neuropeptides constitute a heterogeneous
Curr Neurobiol 2016 Volume 7 Issue 3
group of biologically active peptides that are present in
neurons of both the CNS and PNS. Thus, human skin
and in particular the human sebaceous gland has been
shown to express functional receptors for neuropeptides,
such as corticotropin-releasing hormone, melanocortins,
β-endorphin,
vasoactive
intestinal
polypeptide,
neuropeptide Y and calcitonin gene-related peptide [16].
Specifically, pathologically high levels of substance P and
vasointestinal peptide expression have been shown to play
a role in the pathogenesis of acne vulgaris. In response
to stress, substance P can promote the development of
cytoplasmic organelles in sebaceous cells, stimulate
sebaceous germinative cells, and induce significant
increases in the area of sebaceous glands. It also increases
the size of individual sebaceous cells and the number of
sebum vacuoles for each differentiated sebaceous cell,
all of which suggests that substance P promotes both the
proliferation and the differentiation of sebaceous glands
[17]. The transient receptor potential vanilloid-1 (TRPV1)
expressed in human skin, sebaceous glands in situ and in
SZ95 sebocytes in vitro, when activated by capsaicin, its
agonist, selectively inhibits basal and arachidonic acidinduced lipid synthesis in a dose-, time- and extracellular
calcium-dependent and TRPV1-specific manner [18].
Most recently, using a novel line of transgenic mouse,
it has been possible to demonstrate that Scd3-Creinduced, diphtheria chain A toxin-mediated depletion of
sebaceous lipids resulted in impaired water repulsion and
thermoregulation [19].
Conclusion
All in all, these findings provide increasing evidence
suggesting that key roles are played by neuropeptides
and cutaneous nerves in sebaceous gland secretion and
hence, indirectly, in skin water content through enhanced
protective barrier and reduced water evaporation. These
are promising mechanisms that may become new potential
targets for the development of innovative CNS and/or
PNS products against various types of dry skin problems.
In the meantime and until such products get approval
by authorities, recently identified, scientifically-based,
topical creams may be used for temporary restoration of
lipid-rich epidermal layers and stimulation of endogenous
water transport mechanisms [20,21].
References
1. McGrath JA, Eady RA, Pope FM. Rook's Textbook
of Dermatology (7th ed) Blackwell Publishing 2004;
3.1–3.6.
2. Iozzo RV. Basement membrane proteoglycans: From
cellar to ceiling. Molecular Cell Biology 2005; 6: 646656.
3. Smith MM, Melrose J. Proteoglycans in normal and
healing skin. Adv Wound Care 2015; 4: 152-173.
4. Breitkreutz D, Mirancea N, Nischt R. Basement
membranes in skin: Unique matrix structures with
75
Guertin
diverse functions? Histochemistry and Cell Biology
2009; 132: 1-10.
5. Nakamura K, Morrison SF. A thermosensory pathway
that controls body temperature. Nat Neurosci 2008; 11:
62-71.
6. Prost-Squarcioni C, Fraitag S, Heller M, et al.
Functional histology of dermis. Ann Dermatol Venereol
2008; 135: 15-20.
7. Beitz E. Aquaporins. Handbook of Experimental
Pharmacology Springer, Berlin 2004; 210.
8. Papp A, Romppanen E, Lahtinen T, et al. Red blood
cell and tissue water content in experimental thermal
injury. Burns 2005; 31: 1003-1006.
9. Krogstad AL, Elam M, Karlsson T, et al. Arteriovenous
anastomoses and the thermoregulatory shift between
cutaneous vasoconstrictor and vasodilator reflexes. J
Auton Nerv Syst 1995; 53: 215-222.
10.Blessing WW, Yu YH, Nalivaiko E. Raphe pallidus
and parapyramidal neurons regulate ear pinna vascular
conductance in the rabbit. Neurosci Lett 1999; 270: 33-36.
11.Key BJ, Wigfield CC. The influence of the ventrolateral
medulla on thermoregulatory circulations in the rat. J
Auton Nerv Syst 1994; 48: 79-89.
12.Ootsuka Y, Terui N. Functionally different neurons are
organized topographically in the rostral ventrolateral
medulla of rabbits. J Auton Nerv Syst 1997; 67: 67-78.
13.Owens
NC,
Ootsuka Y,
Kanosue
K,
et
al.
Thermoregulatory control of sympathetic fibres
supplying the rat's tail. J Physiol (Lond) 2002; 543:
849-858.
14.Bielfeldt S, Schoder V, Ely U. Assessment of human
stratum corneum thickness and its barrier properties
by in vivo confocal Raman spectroscopy. IFSCC
Magazine 2009; 12: 1.
15.Thody AJ, Shuster S. Control and function of sebaceous
glands. Physiol Rev 1989; 69: 1-4.
16.Zouboulis CC. Acne and sebaceous gland function.
Clin Dermatol 2004; 22: 360-366.
17.Toyoda M, Nakamura M, Morohashi M. Neuropeptides
and sebaceous glands. Eur J Dermatol. 2002; 12: 422427.
18.Toth BI, Geczy T, Griger Z. Transient receptor potential
vanilloid-1 signaling as a regulator of human sebocyte
biology. J Invest Dermatol 2009; 129: 329-339.
19.Dahlhoff M, Camera E, Schäfer M, et al. Sebaceous
lipids are essential for water repulsion, protection
against UVB-induced apoptosis and ocular integrity in
mice. Development 2016; 143: 1823-1831.
20.Guertin PA. Randomized double-blind study assessing
safety and efficacy of SQIN on xerosis in subjects with
mobility impairment and paralysis. J Dermatol Clin
Res 2016; 4: 1-5.
21.Perricone NV. Formulations topiques à base d’acyl
glutathione 2012.
Correspondence to:
Pierre A Guertin,
Laval University/CHU de Québec,
2705 Laurier Boulevard,
Quebec City, G1V 4G2
QC, Canada.
Tel: 418.525.4444
E-mail: [email protected]
76
Curr Neurobiol 2016 Volume 7 Issue 3