Bleomycin hydrolase downregulation in lesional skin of adult atopic dermatitis patients is independent of FLG gene mutations

Fri, 04/03/2015 - 19:15
Bleomycin hydrolase downregulation in lesional skin of adult atopic dermatitis

Laurence Pellerin, PhD a,b,c Carle Paul, MD, PhD a,b,c,d Anne-Marie Schmitt, MD, PhD e Guy Serre, MD, PhD a,b,c Michel Simon, PhD a,b,c

Source : J ALLERGY CLIN IMMUNOL - 2014

Abstract :

Atopic dermatitis (AD) pathogenesis is still incompletely understood. The major genetic risk factor is nonsense mutations the FLG gene encoding filaggrin. 1 Filaggrin is a key protein for the stratum corneum (SC) barrier functions.
2,3 It is synthesized as 400 kDa precursor named profilaggrin. During the late keratinocyte differentiation, profilaggrin is cleaved by proteases, including calpain-1. The produced filaggrin monomers associate with keratin filaments and promote their aggregation. Then, the monomers are proteolyzed into hygroscopic free amino acids by caspase-14, bleomycin hydrolase (BLMH), and calpain-1. The consequences of FLG nonsense mutations are increased photosensitivity of the lower keratinocytes, enhanced outside-in permeability of the SC, and exacerbated percutaneous immune 
response. 4,5 Other mechanisms beyond FLG mutations certainly are important in the development of AD. Filaggrin expression is downregulated in the epidermis of adult AD patients independently of FLG mutations through the action of proinflammatory cytokines. 6 Also an enhancement of the profilaggrin/filaggrin ratio has been observed in some patients, 6,7 suggesting decreased profilaggrin processing or increased filaggrin degradation. To test this hypothesis, we comparatively analyzed the expression of calpain-1, caspase-14, and BLMH in a cohort of 28 adult AD patients and 28 age- and sex-matched healthy control subjects. The individuals were genotyped for the most common FLG mutations (R501X, 2282del4, S3247X, and R2447X). Total epidermal proteins were prepared and analyzed by Western blotting.

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