September 2013 Altered barrier integrity and enhanced sensitization by filaggrin deficiency


Altered barrier integrity and enhanced sensitization by filaggrin deficiency

B6.Cg-Flg/Rbrc RBRC05850
C.Cg-Flg/Rbrc RBRC05851


a and b. Filaggrin knockout (Flg-/-) mice exhibit an ichthyotic skin phenotype, such as dry and scaly skin, macroscopically on day 4 (arrowheads, scale). c and d. Immunohistochemical staining of mouse dorsal skin on day 4 revealed Flg-targeted mice were completely deficient for profilaggrin and filaggrin.

e and fFlg-/- mice exhibited exaggerated percutaneous immune responses in the context of irritant (e) and allergic contact dermatitis (f) and protein antigen-specific humoral responses (data not shown; see Ref. 3) compared with wild-type (+/+) mice. Changes in ear thickness are displayed after topical application of croton oil (e) and after DNFB challenge on the ears with sensitization (f). *P < 0.05 and **P < 0.01. C57BL/6 background mice were utilized for the above figures.


Filaggrin is a structural protein in the stratum corneum (SC) that is produced as the ~500-kDa precursor protein profilaggrin. Profilaggrin is the major component of keratohyalin granules within the granular layer. Individual filaggrin monomers are released proteolytically during epidermal differentiation, and they contribute to macrofibril generation and the mechanical strength and integrity of the SC. Filaggrin monomers are finally degraded into natural moisturizing factors, which are believed to maintain hydration of the upper SC.Mutations in the filaggrin gene were reported to cause ichthyosis vulgaris [1] and were also identified as a major predisposing factor for atopic dermatitis (AD) [2]. Disruption of the SC barrier caused by filaggrin deficiency may lead to percutaneous allergenic sensitization, a primary event in the pathogenesis of AD [3, 4]. Although various reports have suggested a role for filaggrin in SC barrier formation, the absence of mice specifically lacking filaggrin has prevented further analysis.

Amagai and colleagues recently generated filaggrin knockout mice and revealed that the newborn filaggrin-deficient mice exhibit dry scaly skin, while this phenotype is unrelated to SC water content and transepidermal water loss. Increased penetration of foreign materials and an enhanced percutaneous immune response were also observed in the adult mice [5]. This newly generated knockout mouse strain enables the evaluation of filaggrin function In vivo.


Depositor : Masayuki Amagai, M.D., Ph.D.
Department of Dermatology, Keio University School of Medicine
References : [1] Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro CS, Sergeant A, O’Regan G, Bale SJ, Compton JG, DiGiovanna JJ, Presland RB, Fleckman P, McLean WH. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.Nat Genet.; 38(3): 337-42, 2006.
[2] Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O’Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet.; 38(4):441-6, 2006.
[3] Kubo A, Nagao K, Amagai M. Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases. J Clin Invest.; 122(2):440-7, 2012.
[4] Kubo A, Ishizaki I, Kubo A, Kawasaki H, Nagao K, Ohashi Y, Amagai M. The stratum corneum comprises three layers with distinct metal-ion barrier properties. Sci Rep.; 3:1731, 2013.
[5] Kawasaki H, Nagao K, Kubo A, Hata T, Shimizu A, Mizuno H, Yamada T, Amagai M. Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice. J Allergy Clin Immunol.; 129(6):1538-46.e6, 2012.

Comments are closed.