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Outside-to-Inside (and Now Back to Outside) Pathogenic Mechanisms in Atopic Dermatitis

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	Blumenschein WM, Mattson JD et al. (2007)	and mobility in keratinocytes: a potential role
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See related article on pg 1329

“Outside-to-Inside” (and Now Back to “Outside”) Pathogenic Mechanisms in Atopic Dermatitis

Peter M. Elias1,2 and Martin Steinhoff2,3

The pathogenesis of atopic dermatitis (AD) has been attributed largely to abnormalities in the adaptive immune system, with key roles played by T-help- er 1(Th1)/Th2 cell dysregulation, IgE production, dendritic cell signaling, and mast-cell hyperactivity, resulting in the pruritic, inflammatory dermatosis that characterizes AD (Leung et al., 2004). Accordingly, therapy has been focused on ameliorating Th2-mediated inflammation and pruritus (e.g., Leung, 2000). Indeed, there is emerging evidence that inflammation in AD results first from inherited and acquired insults that converge to alter epidermal structure and function, followed by immune system activation, which in turn has negative consequences for skin-barrier homeostasis. This cycle comprises an “outside– inside–outside” model of AD pathogenesis (Elias et al., in press).

Journal of Investigative Dermatology (2008), 128, 1067–1070. doi:10.1038/jid.2008.88

The epidermis generates an impressive set of critical defensive functions (Elias, 2005; Elias and Choi, 2005) that include the permeability barrier, allowing survival in a potentially desiccating external environment, and an antimicrobial barrier, which simultaneously encourages colonization by nonpathogenic “normal” flora while resisting growth of microbial pathogens (Elias, 2007). The permeability barrier resides in the stratum corneum (SC), where multiple layers of anucleate corneocytes are embedded in an extracellular matrix, enriched in ceramides (Cer), cholesterol, and free fatty acids, arranged as planar lamellar sheets (Elias and Menon, 1991). These lipids, as well as an assortment of hydrolases

important for lipid processing and desquamation and at least two key antimicrobial peptides (Aberg et al., 2007, and references cited therein), are delivered to the extracellular matrix through secretion of epidermal lamellar body contents. Whereas lamellar body– derived proteases and their inhibitors orchestrate the orderly digestion of corneodesmosomes, allowing cells to shed invisibly at the skin surface (Brattsand et al., 2005; Stefansson et al., 2008), the lipid-processing enzymes (β-gluco- cerebrosidase, acidic sphingomyelinase, and secretory phospholipase A2) generate the Cer and free fatty acids that, along with cholesterol, form the extracellular lamellar membrane (Elias and Menon, 1991). Thus, proteases as

1Dermatology Service, Veterans Affairs Medical Center, and Department of Dermatology, University of California, San Francisco, California, USA; 2Department of Dermatology, University of California, San Francisco, California, USA; 3Department of Dermatology, University of Muenster, Muenster, Germany

Correspondence: Dr Peter M. Elias, Dermatology Service (190), VA Medical Center, 4150 Clement Street, San Francisco, California 94121, USA. E-mail: eliasp@derm.ucsf.edu

well as extracellular enzymes may ultimately be involved in the pathophysiology of eczema and pruritus.

Based primarily on the strong association of inherited abnormalities in filaggrin (FLG) expression, atopic dermatitis (AD), at least in Euro-Americans, is now increasingly considered a primary disorder of SC structure and function (Hudson, 2006; Irvine and McLean, 2006; Palmer et al., 2006; Smith et al., 2006; Weidinger et al., 2006). Thus, AD can be considered a disease of primary barrier failure, characterized by both a defective permeability (Proksch et al., 2006, and references therein) and antimicrobial function (Baker, 2006; Boguniewicz and Leung, 2006). Although both of these abnormalities are well-recognized features of AD, they have been widely assumed to reflect downstream consequences of a primary immunologic abnormality (the historical inside–outside view of AD pathogenesis). We and others have long proposed that the permeability-bar- rier abnormality in AD is not merely an epiphenomenon but rather the “driver” of disease activity (i.e., the reverse, outside–inside view of disease pathogenesis) (Elias and Feingold, 2001), because (1) the extent of the permeabil- ity-barrier abnormality parallels severity of disease phenotype in AD, (2) both clinically uninvolved skin sites and skin cleared of inflammation for as long as

|Inﬂammation in AD may begin with insults from without.

5 years continue to display significant barrier abnormalities, (3) emollient therapy comprises effective ancillary therapy, and (4) specific replacement therapy, which targets the prominent lipid abnormalities that account for the barrier abnormality in AD, not only corrects the permeability-barrier abnormality but also comprises effective antiinflammatory therapy for AD (Chamlin et al., 2002; Figure 1).

Still, how loss of FLG (an intracellular protein) provokes a permeability-bar-

www.jidonline.org 1067

COMMENTARY

S. aureus

stored in large quantities in the cytosol

colonization

of corneocytes (Hachem et al., 2002;

Nylander-Lundqvist et al., 1996), the

Cer, free

first step in the cytokine cascade that

Acquired stressors

Toxin- + superantigen-

propose initiates inflammation in

fatty acids,

pH,

RH,

sphingosine

AMP

producing S. aureus

AD (Figure 2).

Another cause of inflammation in

AD doubtless includes sustained anti-

Sustained barrier defect

Th1

Th2

AD lesion

Folliculitus/

gen

ingress through a

defective bar-

impetigo

rier, leading to a T-helper 2 (Th2)-domi-

nant infiltrate (Hudson, 2006). Yet FLG

Cer synthesis

T- B-cell

mutations alone do not provoke AD, as

activation

Inhereited

Keratinocytes

demonstrated in ichthyosis vulgaris, in

defects

Pruritus

protease

which the same singleor double-allele

FLG

dysregulation

FLG mutations reduce FLG content, but

LEKTI

neuropeptides

inflammation (i.e., AD) does not inevi-

Specific Ige

tably occur (Sandilands et al., 2007).

and others

have

suggested that

Scratching/excoriations

certain acquired stressors could elic-

Figure 1. Secondary infections can further aggravate barrier abnormality in atopic dermatitis.

it disease by aggravating the

barrier

abnormality. Indeed, a

barrier-depen-

AD, atopic dermatitis; AMP, adenosine monophosphate; Cer, ceramide; FLG, filaggrin; LEKTI,

dent increase in pH (and serine protease

lymphoepithelial Kazal-type related trypsin inhibitor; PS, psychological stress; RH, relative humidity;

Th1,T-helper 1;Th2,T-helper 2 (Modified from Elias et al., in press.)

activity) likely accounts for the precipi-

tation of AD following the use of neu-

tral-to-alkaline soaps (Figure 1) (Cork et

rier abnormality is not known. In addi-

the multiple serine proteases in SC,

al., 2006). Likewise, prolonged expo-

tion, it is not clear what drives barrier

which all exhibit neutral-to-alkaline

sure to reduced environmental humid-

dysfunction in the skin of AD patients

pH optima (Brattsand et al., 2005;

ity, a well-known risk factor for AD,

without a FLG mutation. Although it

Stefansson et al., 2008; Steinhoff et al.,

likely accelerates transcutaneous water

has been hypothesized that loss of FLG

2005). Increased serine protease activ-

loss rates across defective SC in AD,

could

cause

corneocyte

deformation,

ity could generate the active forms of

further aggravating the barrier abnor-

the barrier

abnormality

likely

the primary cytokines IL-1α and IL-1β

mality.

Finally,

psychological

stress,

is linked to lack of FLG as a substrate

from their 33-kDa pro-forms, which are

which

aggravates permeability-barrier

for proteolytic processing and further

deimination into polycarboxylic acids,

such as pyrrolidine carboxylic acid and

trans-urocanic acid. These metabo-

Barrier

lites normally act as osmolytes (natural

perturbation

moisturizing

factors),

drawing

water

Stratum corneum

into corneocytes, partially account-

ing for corneocyte hydration. Hence,

Inhibitory Ions

Cer, FLG

Cytokines/growth factor

Proteases

the most immediate result of FLG defi-

ciency is decreased SC hydration, a

well-recognized feature of AD. A steep-

Lamellar body

Lipid and hBD2

DNA synthesis

er water gradient would inexorably

secretion

accelerate transcutaneous

water

loss,

particularly if a paucity of extracellular

Epidermis

Permeability and antimicrobial

Epidermal

Cytokines/

lipids results in decreased water-retain-

barrier restoration

hyperplasia

growth factors

ing ability. However, either corneocyte

flattening or decreased SC hydration

Chemokines

can suffice to enhance antigen penetra-

tion. We suspect that another mecha-

nism

operative, because another

Dermis

Th2 cytokines

inevitable

consequence

of decreased

Inflammation

downstream production of polycarbox-

ylic acid metabolites is an increase in

Figure 2.“Outside–inside–outside” model ofAD. Cer, ceramide; FLG, filaggrin; hBD2, human β-defensin-2;

the SC pH (Krien and Kermici, 2000),

Th2,T-helper 2. (From Figure 2. Cer, ceramide; FLG, filaggrin; hBD2, human β-defensin-2;Th2,T-helper 2.

sufficient

increase

the

activities of

(From Steinhoff et al., 2005; modified from Elias et al., in press.)

1068 Journal of Investigative Dermatology (2008), Volume 128

COMMENTARY

function in humans (Altemus et al., 2001), is both a well-known precipitant of AD and a cause of resistance to therapy. Moreover, a dysregulation of proteases, highly expressed by keratinocytes, protease inhibitors, and protease-acti- vated receptors, may be important for neuronal–epidermal communication during barrier dysfunction (Demerjian et al., 2008; Hachem et al., 2006; Steinhoff et al., 2000, 2005).

Despite accumulating evidence in support of a barrier-initiated pathogenesis of AD, recent studies suggest specific mechanisms whereby Th2generated cytokines could also further aggravate AD. As described in this issue by Kurahashi et al. (2008), exogenous applications of the Th2 cytokine, IL-4, impede permeability-barrier recovery after acute perturbations. The basis for the negative effects of IL-4 could include the prior observation by these authors that exogenous IL-4 inhibits Cer synthesis (Hatano et al., 2005). But IL-4 also inhibits expression of both FLG (Howell et al., 2007) and desmoglein 3 (Kobayashi et al., 2004), which also could further compromise barrier function, completing a potential out- side–inside–outside pathogenic loop in AD (Figure 2). Furthermore, nerves may be activated by “barrier stressors” such as UV light, toxic or allergic agents, and microbial agents. Therefore, nervederived mediators could also modulate enzyme production, antimicrobial peptide (defensin) generation, pH changes, or SC humidity, thereby influencing keratinocyte function (Paus et al., 2006; Roosterman et al., 2006; Steinhoff et al., 2006).

Together, the converging pathogenic features described above create a strong rationale for the deployment of specific strategies to restore barrier function in AD. When used under nursing supervision, moisturizers have been shown to reduce topical steroid usage (Cork et al., 2003). Of various barrier-repair approaches, a mixture of the three SC lipids in a Cer-dominant formulation (TriCeram, Osmotics Cosmeceuticals) demonstrated improved clinical status, permeability-barrier function, and SC integrity when this technology was substituted for standard moisturizers in children with severe, recalcitrant AD

(Chamlin et al., 2002). More recently, a higher-strength, FDA cleared formulation (EpiCeram cream, Ceragenix Pharmaceuticals) demonstrated efficacy that was comparable to that of a midpotency steroid (fluticasone; Cutivate cream) in an investigator-blinded, multicenter clinical trial of pediatric patients with moderate to severe AD (Sugarman and Parish, in press). These studies, although still preliminary, suggest that correction of the lipid biochemical abnormality that is responsible for the barrier defect in AD could also downregulate the further inside- to-outside alterations provoked by IL-4 and could comprise a new or ancillary approach to the therapy of AD.

CONFLICT OF INTEREST

Dr Elias is a co-inventor of Cer-dominant formulation (TriCeram, Osmotics Corp.), a patented technology, and an officer of Ceragenix Pharmaceuticals, the licensee of this technology. Dr Steinhoff states no conflict of interest.

ACKNOWLEDGMENTS

We gratefully acknowledge the superb editorial assistance of Joan Wakefield and Jerelyn Magnusson, including preparation of the graphics. This work was supported by National Institutes of Health grant AR19098, Department of Defense grant W81XWH-05-2-0094, and the Medical Research Service, Department ofVeterans Affairs, grants DFG (STE 1014/2-2) (M.S.) and SFB 293 (M.S.). No company provided support for this article.

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1070 Journal of Investigative Dermatology (2008), Volume 128

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