Unveiling the Interplay: Mast Cells and the Dynamic Skin Environment

Abstract

Mast cell (MC) progenitors enter the skin and mature in the surrounding skin microenvironment during embryogenesis, and they occupy stable territories until inflammation occurs. Mast cell (MC) progenitors mature in the surrounding skin microenvironment during embryogenesis. In the skin, commensal bacteria work together with skin resident cells, especially keratinocytes, to retain and differentiate mast cells. This effect is due to keratinocytes' TLR2 sensing of the microbiome and the consequent release of Stem cell factor (SCF), an essential growth factor for MCs. We published that skin commensal bacteria work together with skin resident cells, especially keratinocytes, to retain and differentiate mast cells into the skin. We demonstrated that this effect is due to keratinocytes' TLR2 sensing of the microbiome.  In fact,  hr/hr mice that are hairless have a skin-increased number of mature and proliferating MCs that correlates with a more gram positive-microbiome than their littermates. When hr/hr were backcrossed into Tlr2^-/-  (so they cannot sense the gram-positive commensals), the number of MCs in the skin dramatically decreased. While baseline keratinocyte SCF expression is essential to retain MCs in the skin, TLR2 stimulation by gram-positive skin microbiome promotes SCF keratinocyte production, which enhances skin maturation and tissue proliferation of MCs.

MCs are known to control skin inflammation. Activation and degranulation of mast cells (MCs) are essential in innate and adaptive immunity; however, strict activation control is critical to prevent unwanted inflammation. The demand for MC regulation is significant, especially at the skin interface, where MCs are required to fight pathogens but should not react to commensal bacteria. Interestingly, MCs assume a tolerant phenotype in the skin microenvironment to reduce unnecessary inflammation in contact with beneficial commensal bacteria via crosstalk with dermal fibroblasts and the downregulation of their TLR2 receptor. The increased communication between hMCs and dFBs in the absence of the TLR2 receptors induces dramatic changes in dFB populations and hMC differentiation. To further understand how bacteria tolerance is established in hMCs by the presence of dFBs, we performed RNA-Seq analysis of MCs stimulated with gram-positive bacterial supernatant in the presence or absence of dFB. We co-cultured MC for a week with dFB, separated them, and challenged them with LTA, S. Epidermidis, and S. Aureus 113. The combined analysis of single cells RNA-Seq and bulk RNA-Seq confirmed that dFB activates different pathways to induce MC tolerance to gram-positive commensal bacteria. 

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https://us02web.zoom.us/j/81291723159?pwd=V0wwZUlXdVhob2cydm82eTI2RDRpdz09

Meeting ID: 812 9172 3159

Passcode: 793216