Piel (Barc., Ed. impr.) 2011;26(6):259–262

PIELFORMACION CONTINUADA EN DERMATOLOGIA

www.elsevier.es/piel

Editorial

Infrared A radiation effects on the skin

Efectos de la radiacion infrarroja A en la piel

Peter Schroeder, Jean Krutmann *

Environmental Health Research Institute (IUF) at the Heinrich-Heine-University, Dusseldorf, Germany

Extrinsic skin aging has for many years been mainly attributed

to ultraviolet (UV) radiation. More recently it has become

evident that other parts of the solar electromagnetic spectrum

contribute as well. Among these, infrared radiation, especially

infrared A has received increasing attention. These have

summarized the current knowledge about the epidemiological

evidence, molecular principles and prevention/protection, as

it concerns skin aging induced by infrared A.

Infrared radiation

Physical basics, natural and artificial sources

Solar radiation is filtered by the earth’s atmosphere; the part

reaching the earth surface includes the wavelengths from 290

– 4000 nm and is divided into three bands: ultraviolet radiation

(UV, 290-400 nm), visible light (400-760 nm) and infrared

radiation (IR, 760-4000 nm). Infrared radiation is further

subdivided into IRA (g = 760-1440 nm), IRB (g = 1440-

3000 nm) and IRC (g = 3000 nm-1 mm).

While the photon energy of IR is lower than of UV, the total

amount of solar energy reaching human skin contains app.

54% IR while UV only accounts for 7%.1 Most of the IR radiation

lies within the IRA band (app. 30% of total solar energy), which

deeply penetrates human skin while IRB and IRC only affect

the upper skin layers. In comparison IRA penetrates into the

skin better than UV, with appr. 50% reaching the dermis.1-3

The main source of IR radiation is the sun; the actual solar

dose reaching the skin is influenced by several factors: ozone

layer, position of the sun, latitude, altitude, cloud cover and

* Corresponding author.E-mail address: krutmann@uni-duesseldorf.de (J. Krutmann).

0213-9251/$ – see front matter # 2010 Elsevier Espana, S.L. All rightsdoi:10.1016/j.piel.2011.01.012

ground reflections. Based on these parameters it should be

noted, that the overall composition of sunlight, e.g. in terms of

the UV/IRA ratio is changing throughout the day. In addition to

natural sunlight, artificial IR sources are constantly gaining

importance; they are used for therapeutic as well as for

lifestyle purposes. While therapeutical use of IRA provides

beneficial effects for example in wound healing, lifestyle

motivated application of IRA, e.g. for ‘‘wellness’’ irradiations

or for means of skin rejuvenation appear to be quite

paradoxical.4

Infrared Radiation and Skin Aging

A role of IR radiation for premature skin aging has already

been described over 20 years ago by L. Kligman.5 She has been

first to report that infrared radiation enhances UV induced

skin damage in guinea pigs. This prompted her to investigate

the effect of IR alone and as a consequence she could

demonstrate that IR leads to elastosis, with ‘‘IR inducing

the production of many fine, feathery fibers’’ and ‘‘a large

increase in ground substance, a finding also seen in

actinically damaged human skin’’. From these observations

she has concluded that IR radiation contributes to skin aging.

It took —however— almost 20 years until the underlying

molecular mechanisms could be identified.

Molecular Mechanisms

Schieke et al reported in 2002 that low, physiologically

relevant doses of IRA lead to a disturbance of the dermal

extracellular matrix. IRA irradiation results in an induction of

Matrixmetalloproteinase-1 (MMP-1) in vitro in human dermal

reserved.

IRA IRB IRC

Epidermis

Dermis

Subcutis

Figure 1 – Infrared-A-induced signal transduction. IRA

radiation leads to an increase amount of mitochondrial

ROS which in turn leads to initiation of retrograde

signaling, finally resulting in an increased expression of

MMP-1 mRNA and protein and a decreased expression of

Col1a1.

Piel (Barc., Ed. impr.) 2011;26(6):259–262260

fibroblasts while expression of the respective tissue inhibitor

TIMP-1 was not increased. This finding has since then be

confirmed in independent studies by different workgroup in

vitro and in vivo.6,7

Matrixmetalloproteinases (MMPs) are zinc-dependent

endopeptidases responsible for the degradation of extrace-

llular matrix components such as collagen and elastin. Under

physiological conditions, MMPs are part of a coordinate

network and are precisely regulated by their endogenous

inhibitors, tissue inhibitors of MMPs (TIMPs). The unbalanced

activity of MMPs with excessive proteolysis is thought to be a

major pathophysiological factor in extrinsic skin aging. The

increased expression of MMPs without a respective increase in

TIMP expression results in cleavage of fibrillar collagen, and

thus impairs the structural integrity of the dermis.8-10

This impairment can be partially countered by an increased

expression of collagen itself. It is therefore important to note,

that IRA has recently been found to decrease the expression of

the dominant human collagen gene Col1a1 in vitro and in

vivo.6,11

Taken together IRA disturbs the collagen equilibrium of the

skin in two ways: a) by increasing the amount/activity of MMP-

1 which results in an increased collagen degradation, and b) by

decreasing de novo synthesis of collagen.12

While the biological endpoints of IRA irradiation resemble

those found after UV irradiation, the underlying cellular

molecular processes are completely different. This is parti-

cularly evident if UVA and IRA are being compared: the primal

event in both cases is an increased amount of reactive oxygen

species, which on a first glare seems to indicate a similarity

rather than a difference. More detailed analysis —however—

revealed huge differences between UVA and IRA. UVA induces

an increased production of ROS by NADPH-Oxidases, which

are located in the cytoplasma membrane13 and in addition

repetitive UVA irradiation results in damage to the mito-

chondrial DNA (mtDNA).14 IRA, on the other hand acts via a

disturbance of the mitochondrial electron transport chain

(mtETC). This multiprotein facility, driven by reduction

equivalents (NADH/H+ and FADH2), is responsible for energy

conservation by transferring electrons to oxygen while

building up a electrochemical proton gradient across the

inner mitochondrial membrane which in turn fuels the

production of ATP from ADP and Pi. As this process is not

error free, relatively small amounts of ROS are always

generated. Upon IRA irradiation this amount is significantly

increased.4

ROS are often recognized only as damaging agent, but they

are well known to function in terms of cellular signaling.

Reactive oxygen species (ROS) can serve to trigger molecular

signaling responses and several studies indicate that ROS

cause an inactivation of protein-tyrosine phosphatases (PTPs)

by oxidizing conserved cysteine residues in the active sites of

PTPs and thereby lead to a net increase in kinase phosphory-

lation/activation.15

After IRA irradiation not only the mitochondrial but the

cellular ROS levels are increased and a disturbance of the

cellular glutathione (GSH) equilibrium was observed.16 GSH is

one of the most important endogenous antioxidants, it can

prevent or repair oxidative damage, and as a consequence it is

oxidized itself, forming the glutathione dimer (GSSG). In this

regard, IRA irradiation leads to a significant shift of the GSH/

GSSG equilibrium towards the oxidized form.16

IRA-induced ROS production is not just a byproduct of the

irradiation but of functional relevance because boosting the

cellular antioxidative defense by increasing the cellular GSH

content abrogated the IRA induced upregulation of MMP-1.16

In addition, use of specific antioxidants in cell culture has also

been shown to decrease the IRA induced effects.

Mitochondria are known to act as a hub for cellular

signaling with disruption of the mtETC being a prominent

inducer of such retrograde (i.e. from mitochondria to nucleus)

signaling.17 (fig. 1) In contrast to anterograde signaling

processes here the nuclear gene expression is regulated by

events originating in the mitochondria. The IRA-induced

increase in mitochondrial ROS was recently found to initiate

such a retrograde signaling cascade.

Downstream of mitochondrial ROS, the IRA radiation

induced signaling pathway relevant for MMP-1 induction

has been found to involve the activation of MAPKinases. Three

distinct MAPK pathways have been characterized: the extra-

cellular signalregulated kinase 1/2 (ERK1/2) pathway (Raf-

MEK1/2-ERK1/2), and the c-Jun N-terminal kinase (MEKK1/3-

MKK4/7-JNK1/2/3) and p38 (MEKK-MKK3/6-p38 a-d) pathways

also termed stress-activated protein kinases (SAPKs). The

ERK1/2 pathway is primarily induced by mitogens such as

growth factors, whereas the SAPK pathways are predomi-

nantly induced by inflammatory cytokines as well as

environmental stress such as UV, heat and osmotic shock.

Activated MAPKs translocate to the nucleus, where they

phosphorylate and activate transcription factors such as c-

Jun, c-Fos, ATF-2 and ternary complex factors (TCF) leading to

the formation and activation of homo- or heterodimeric forms

of the transcription factor AP-1. The promoter region of MMP-1

carries multiple AP-1-binding sites. For IRA, it has been

demonstrated that ERK1/2 and p38 are activated in dermal

fibroblasts, but that only inhibition of ERK1/2 activation

subdues the IRA induced increase of MMP-1.

Although up to now the main research focus has been on

MMP-1 and Col1a1 it is very likely that the IRA induced[()TD$FIG]

Piel (Barc., Ed. impr.) 2011;26(6):259–262 261

activation of MAPKinases affects the regulation of other genes

as well. Indeed, several additional effects of IRA are known:

Kim et al. reported, that infrared exposure is involved in

neoangiogenesis in human skin, because IRA induces an

angiogenic switch by altering the balance between the

angiogenic inducer VEGF and the angiogenic inhibitor TSP-

2.18 Interestingly, increased neoangiogenesis is a prominent

feature of photoaged human skin.19 Others found that IRA

irradiation led to a decrease in epidermal proliferation,

Langerhans cell density and contact hypersensitivity reaction

in mice20 and a subsequent study by the same group indicates,

that IRA influences cutaneous wound repair by altering the

levels of transforming growth factor (TGF)-b1 and MMP-2.21

Yet another study showed an influence of IRA on protein

expression of ferritin: an increased ferritin expression was

detected after IRA irradiation of keratinocytes and fibro-

blasts.22 Ferritin is involved in the cellular antioxidative

defense and the induction of this putative defense system

in human skin most likely reflects a cellular response to

oxidative processes triggered by IRA. Frank et al showed that

IRA interferes with apoptotic pathways, namely with the

mitochondrial apoptosis pathway,23 and reported that IRA

signals via p5324. The abrogating effect of IRA on apoptosis

induced by lethal doses of extrinsic factor has recently been

confirmed by another study.25

Dosimetry of IRA: Human dermal fibroblasts withstand IRA

doses up to at least26 1200 J/cm2, but the gene regulatory

effects can already be observed at much lower, physiologically

relevant dosage (e.g., 5421, 24011, or 36016 J/cm2). Increased

levels of cytosolic and mitochondrial ROS were detected16

even after a treatment with 30 J/cm2.

IRA chromophores: While the endogenous chromophores for

IR are very likely to be part of the mtETC27 and remain to be

identified, several exogenous chromophores for IR are known.

They are used for therapeutic purposes, e.g. in photodynamic

therapy, and include palladium-bacteriopheophorbide and

indocyanine green.28,29

Protection against IRA: Up to now photoprotection of human

skin identical to protection against UVB and/or UVA radiation.

The studies discussed above indicate, however, that protec-

tion against IRA radiation has to be included in order to

achieve complete protection.

In this regard antioxidants appear to be promising. Based

on the fact, that mtROS are functionally relevant in the IRA

induced effects, antioxidants that target the mitochondria

theoretically represent potential IRA protective substances.

Indeed, it has been demonstrated in vitro and in vivo that such

specific antioxidants protect against detrimental IRA effects,

e.g. IRA-induced MMP-1 expression.7

In contrast, there are currently no chemical or physical UV

filters available which are suited for commercial suncare

products, and which have been shown to provide IRA

protection.

The protective effect of textiles remains to be evaluated in

terms of IRA protection. There is, however, data available

showing that use of a black cloth at least partially provides

IRA-protection.18

Finally the topic of avoidance has to be discussed. Up to

now, there is no information source available that would

provide a measure on the actual IRA load that would be

comparable to the well established UV-index. Establishing a

respective IRA-index might be a considerable contribution.

Concluding Remarks

As skin aging is a complex processes it is not surprising that

ongoing research efforts uncover more and more environ-

mental factors enfolding detrimental effects on the skin.

Regarding natural sunlight or artificial sources of its compo-

nents there is longer doubt that in addition to UV, IRA

protection has to be taken into account.

IRA photoprotection requires specialized strategies with

topical application of mitochondrially-targeted antioxidants

being a promising option.

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