Filaggrin knockdown and Toll‐like receptor 3 (TLR3) stimulation enhanced the production of thymic stromal lymphopoietin (TSLP) from epidermal layers

Abstract

Keratinocytes constitute the first-line barrier against exogenous antigens and contain Toll-like receptors (TLRs), which function as pattern-recognition molecules to activate antimicrobial innate immune responses. In an effort to ascertain whether or not filaggrin (filament-aggregating protein) expression affected the TLR-mediated responses of keratinocytes, we transfected filaggrin siRNA into HaCaT human keratinocyte cells and determined that thymic stromal lymphopoietin (TSLP) and IL-6 secretion were increased by poly(I:C) stimulus. Additionally, TSLP expression is increased in filaggrin knockdown as well as TLR3 stimulation in reconstituted human epidermal layers. Therefore, the findings of this study show that reduced filaggrin levels may influence innate immune responses via TLR stimuli and may contribute to the pathogenesis of inflammatory skin disease via TSLP expression.

Requirement of MyD88 signaling in keratinocytes for Langerhans cell migration and initiation of atopic dermatitis‐like symptoms in mice

“…Again, the production of CCL2, GM-CSF, and CXCL1 was strongly dependent on MyD88 in keratinocytes of solvent-treated mice, whereas IL-1a and TNF-a were only marginally and TSLP secretion was not affected by MyD88 deficiency. Since TLR3/TRIF or IRF3 activation is able to induce TSLP [39,40] and Th2 cytokines boost TLSP expression [41], it might be possible that enhanced TRIF activation in our setting, might lead to increased TLSP levels.Repeated tape-stripping and application of OVA in vivo led to enhanced expression of all cytokines analyzed even from keratinocytes of noninvolved distant skin in vitro in a MyD88-dependent manner (Fig. 5B).…”

Filaggrin Mutations and the Atopic March

“…Dermal exposure to TLR2 and TLR 4 agonists led to a decrease in airway hyperresponsiveness and mucous production [ 36 ], suggesting a protective role for TLR activation to stop the atopic march.. However, in keratinocytes with decreased fi laggrin expression, increased IL-6 and TSLP were detected following poly I:C stimulation of TLR3 [ 37 ]. As noted previously, TSLP derived from the skin has been implicated in the development of atopic asthma.…”

Flaky Tail Mouse as a Novel Animal Model of Atopic Dermatitis: Possible Roles of Filaggrin in the Development of Atopic Dermatitis

“…This phenomenon occurs independently of the environment, adaptive immune system and underlying epithelial barrier defect (Briot, et al, 2009, Briot, et al, 2010. In vitro study using human keratinocyte cell line HaCaT cells and reconstituted human epidermal layers transfected with filaggrin siRNA showed increased production of TSLP via toll-like receptor (TLR) 3 stimulation (Lee, et al, 2011). These findings suggest that reduced filaggrin levels may influence innate immune response via TLR stimuli and elevate TSLP, leading to AD-like skin lesions.…”