Abstract
Mast cells (MCs) play critical roles in allergic and inflammatory reactions and contribute to multiple pathologies in the skin, in which they show increased numbers, which frequently correlates with severity. It remains ill-defined how MC accumulation is established by the cutaneous microenvironment, in part because research on human MCs rarely employs MCs matured in the tissue, and extrapolations from other MC subsets have limitations, considering the high level of MC heterogeneity. Thymic stromal lymphopoietin (TSLP)—released by epithelial cells, like keratinocytes, following disturbed homeostasis and inflammation—has attracted much attention, but its impact on skin MCs remains undefined, despite the vast expression of the TSLP receptor by these cells. Using several methods, each detecting a distinct component of the apoptotic process (membrane alterations, DNA degradation, and caspase-3 activity), our study pinpoints TSLP as a novel survival factor of dermal MCs. TSLP confers apoptosis resistance via concomitant activation of the TSLP/ signal transducer and activator of transcription (STAT)-5 / myeloid cell leukemia (Mcl)-1 route and a newly uncovered TSLP/ c-Jun-N-terminal kinase (JNK)/ B-cell lymphoma (Bcl)-xL axis, as evidenced by RNA interference and pharmacological inhibition. Our findings highlight the potential contribution of TSLP to the MC supportive niche of the skin and, vice versa, highlight MCs as crucial responders to TSLP in the context of TSLP-driven disorders.
Highlights
Mast cells (MCs) are tissue-resident key effector cells of Immunoglobulin E (IgE)-mediated allergic and inflammatory responses, including common skin disorders, such as atopic dermatitis (AD) and psoriasis [1,2,3,4,5,6]
After having confirmed that the Thymic stromal lymphopoietin (TSLP) receptor is expressed at mRNA and protein level (Figure S1), we determined whether TSLP influences skin MC survival
We found that B-cell lymphoma (Bcl)-xL and myeloid cell leukemia (Mcl)-1 were distinctively upregulated by TSLP
Summary
Mast cells (MCs) are tissue-resident key effector cells of Immunoglobulin E (IgE)-mediated allergic and inflammatory responses, including common skin disorders, such as atopic dermatitis (AD) and psoriasis [1,2,3,4,5,6]. The stem cell factor (SCF)/KIT (CD117) axis is believed to have a critical impact on MC survival, but other factors are likely to contribute, their relevance has remained less defined. MCs are characterized by excellent survival properties in their natural skin habitat [12,13]. This property is maintained ex vivo, as skin MCs show remarkable persistence, even in the absence of SCF. Several studies have indicated that the protection from cell death requires factors other than SCF [14,15,16,17]
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