Thymic stromal lymphopoietin production induced by skin irritation results from concomitant activation of protease‐activated receptor 2 and interleukin 1 pathways

Abstract

Summary Background Thymic stromal lymphopoietin (TSLP) mediates proallergic T helper 2‐type responses by acting on leucocytes. Endogenous pathways regulating TSLP production are poorly defined. Objectives To uncover the mechanisms by which skin barrier disruption elicits TSLP production and to delineate the level at which individual mechanistic components may converge. Methods A combination of primary keratinocytes, skin explants and in vivo strategies was employed. Murine skin was tape stripped in the presence of neutralizing antibodies or antagonists. Cells and explants were stimulated with interleukin (IL)‐1 and protease‐activated receptor 2 agonist (PAR‐2‐Ag). TSLP levels were quantified by enzyme‐linked immunosorbent assay and real‐time quantitative polymerase chain reaction. Chromatin immunoprecipitation and promoter reporter assays were used to examine recruitment and functional activity of nuclear factor kappa B (NF‐κB) at the TSLP promoter. Results TSLP induction in mouse skin occurred in a PAR‐2‐ and IL‐1‐dependent manner. This scenario was duplicated by exogenous IL‐1 plus PAR‐2‐Ag vs. each stimulus alone. Joint activity of PAR‐2 and IL‐1 was also observed in human keratinocytes. The TSLP promoter was identified as the target of PAR‐2/IL‐1, whereby PAR‐2 activation augmented the recruitment of NF‐κB and transcriptional activation over IL‐1 alone. Combined treatment showed activity at concentrations of IL‐1 unable to elicit NF‐κB activity on their own. Conclusions Skin barrier disruption activates the IL‐1 and the PAR‐2 pathways, which act in concert to activate the TSLP promoter and possibly other inflammatory genes. Awareness of this combined activity may permit a more flexible clinical management by selective targeting of either pathway individually or collectively. What's already known about this topic? Thymic stromal lymphopoietin (TSLP) is rapidly induced upon skin perturbation and mediates proallergic T helper 2‐type responses by acting on leucocytes. Endogenous control of TSLP expression is poorly understood, but interleukin (IL)‐1 is one regulator in the cutaneous environment In addition to IL‐1, protease‐activated receptor 2 (PAR‐2) organizes central inflammatory pathways in the skin. What does this study add? IL‐1 and PAR‐2 pathways cooperate in driving TSLP production in mice and humans. Pathway integration occurs at the level of the TSLP promoter through enhanced recruitment and transcriptional activation of nuclear factor kappa B. When PAR‐2 is co‐stimulated, very low IL‐1 levels (inactive by themselves) can induce biologically meaningful responses in the skin environment. What is the translational message? Physical skin irritation results in robust TSLP production by simultaneous activation of PAR‐2 and IL‐1 pathways.

Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK

“…Following up on this finding, we recently reported that TSLP efficiently maintains survival of skin MCs by acting through a complex mechanism composed of two parallel axes, i.e., STAT5/Mcl-1 and JNK/Bcl-xl [ 44 ]. While being renowned for its Th2 skewing potential, TSLP can, in addition to these more long-term effects, act as an epithelial alarmin, that is swiftly synthesized and released upon tissue damage, including microbial challenge, trauma, and physical or chemical insults [ 45 , 46 , 47 ]. Under these circumstances, TSLP can act acutely, and MCs are ideally positioned in tissues to swiftly respond to and integrate signals from infectious agents, allergens, drugs and tissue-derived alarmins.…”

Olive‐Oil‐Derived Polyphenols Effectively Attenuate Inflammatory Responses of Human Keratinocytes by Interfering with the NF‐κB Pathway

“…TSLP is associated with inflammatory processes of the skin and disorders like atopic dermatitis . To induce TSLP production, keratinocytes were stimulated with IL‐1β and TLR3‐l based on previous studies from our laboratory .…”

“…Thymic stromal lymphopoietin (TSLP), an influential keratinocyte‐derived mediator, is triggered by physical, chemical, or biological disturbance of skin homeostasis . It is directly associated with inflammatory and hypersensitivity responses occurring at barrier surfaces, as well as with Th2 immunity and chronic dermatoses like atopic dermatitis (AD) and psoriasis .…”

Thymic stromal lymphopoietin, protease‐activated receptor 2 and interleukin 1 are involved in the relationship between skin irritation and atopic dermatitis

“…In summary, the study by Redhu et al . shows how skin irritation can aggravate atopic eczema or trigger flares: IL‐1 and PAR‐2 pathways are activated and then cooperate in driving TSLP production, which secondarily promotes Th2 differentiation, Th2 cell proliferation as well as the production of Th2 cytokines .…”