Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency.
BACKGROUND
Filaggrin (FLG) mutations result in reduced stratum corneum (SC) natural moisturizing factor (NMF) components and consequent increased SC pH. Because higher pH activates SC protease activity, we hypothesized an enhanced release of proinflammatory IL-1 cytokines from corneocytes in patients with atopic dermatitis (AD) with FLG mutations (AD(FLG)) compared with that seen in patients with AD without these mutations (AD(NON-FLG)).


OBJECTIVE
We sought to investigate SC IL-1 cytokine profiles in the uninvolved skin of controls and patients with AD(FLG) versus patients with AD(NON-FLG). We also sought to examine the same profiles in a murine model of filaggrin deficiency (Flg(ft)/Flg(ft) [Flg(delAPfal)] mice).


METHODS
One hundred thirty-seven patients were studied. NMF levels were ascertained using confocal Raman spectroscopy; transepidermal water loss and skin surface pH were measured. IL-1α, IL-1β, IL-18, IL-1 receptor antagonist (IL-1RA), and IL-8 levels were determined in SC tape strips from 93 patients. All subjects were screened for 9 FLG mutations. Flg(ft)/Flg(ft) (Flg(delAPfal)) mice, separated from maFlg(ft)/maFlg(ft) (flaky tail) mice, were used for the preparation and culture of primary murine keratinocytes and as a source of murine skin. RT-PCR was performed using primers specific for murine IL-1α, IL-1β, and IL-1RA.


RESULTS
SC IL-1 levels were increased in patients with AD(FLG); these levels were inversely correlated with NMF levels. NMF values were also inversely correlated with skin surface pH. Skin and keratinocytes from Flg(ft)/Flg(ft) mice had upregulated expression of IL-1β and IL-1RA mRNA.


CONCLUSIONS
AD(FLG) is associated with an increased SC IL-1 cytokine profile; this profile is also seen in a murine homologue of filaggrin deficiency. These findings might have importance in understanding the influence of FLG mutations on the inflammasome in the pathogenesis of AD and help individualize therapeutic approaches.
Coronel Institute of Occupational Health, Academic Medical Center, Amsterdam, the Netherlands.
Sanja
S
Kezic
Gráinne M
GM
O'Regan
René
R
Lutter
Ivone
I
Jakasa
Ellen S
ES
Koster
Sean
S
Saunders
Peter
P
Caspers
Patrick M J H
PM
Kemperman
Gerwin J
GJ
Puppels
Aileen
A
Sandilands
Huijia
H
Chen
Linda E
LE
Campbell
Karin
K
Kroboth
Rosemarie
R
Watson
Padraic G
PG
Fallon
W H Irwin
WH
McLean
Alan D
AD
Irvine
D000293:Adolescent; D000483:Alleles; D000818:Animals; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000091344:Filaggrin Proteins; D005838:Genotype; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007223:Infant; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D012867:Skin / Q000378:metabolism
D016207:Cytokines; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007375:Interleukin-1; D007381:Intermediate Filament Proteins