Despite the importance of mast cells (MCs) in innate and acquired immunity, their development and recruitment into the skin is not well understood. Our findings suggest that the skin microbiome has a strong influence on migrating and, in particular, maturing MCs in the skin. Based on our preliminary data, we have demonstrated that bacterial products at the skin surface participate in the regulation of MC antimicrobial functions, homing to the skin, and help them respond to their survival growth factor, SCF. Even more important is the ability of the microbiome to induce an anti-inflammatory phenotype on human MCs that contributes to maintaining skin homeostasis, which helps avoid unnecessary inflammation. Antibiotic exposure, and a pseudo-aseptic environment, have the potential to alter the skin microbiome selectively and may be the cause of the increasing incidence of human disorders such as atopic dermatitis. We hypothesize that bacterial products, increase mast cell recruitment and are responsible for maintaining high levels of antimicrobial peptides (AMPs) and a low pro-inflammatory cytokine profile. A humanized mouse model system will enable the simultaneous study of both human MC migration pathways and TLR innate immune responses in a genetically adaptable organism, thereby translating our findings to human skin. We propose the following: a) Determine whether bacterial products from the skin microbiome are required for normal mast cell localization and function. The use of germ free and antibiotic treated mice will allow us to test whether disruption of the normal skin microbiome results in improper localization and function in vivo and whether reconstituting the microbiome can reverse these effects. Because human MCs may have a different sensitivity to the microbiome, we will test our findings on human MCs (huMCs) to provide a foundation for future translational research. b) Clarify the signaling pathways that are responsible for MC sensing the skin microbiome and how activation of these pathways affects MC function. We will focus on characterizing the MC receptors involved in sensing bacterial byproducts. The aspects to be studied: 1. Commensal activity directly on MC receptors (TLR ligands), 2. Commensal activity on keratinocytes that generate ligands (SCF, IL-1, and S1P) for MC receptors, and 3. Commensal activity on Endothelial cells (SCF) that generate ligands for MC receptors. c) Determine how MC interaction with the microbiome modulates intracellular pathways in skin MCs and affects their function. Our preliminary data show that bacterial byproducts modulate huMCs maturation and activation through NF-kB, S1P and intracellular sphingokinases (Sphks) pathways to produce S1P; we have found that LTA and other commensal fractions induce the expression of specific miRNAs that interfere with TLR-NF-kB signaling.

Public Health Relevance

The concept of microbiome, being part of the human organism, also implies the recognition that the immune system has co-evolved with the commensal microbes, and developed a system of mutual identification and cooperation; this applies to skin microbiome and mast cells (MCs). We provide evidence that the presence of bacterial products at the skin surface participates in the regulation of MC antimicrobial function, drives them to the skin, helps their survival, and most important, creates an anti-inflammatory environment. Our work will reveal significant new aspects of MC function with important implications for diseases such as atopic dermatitis and psoriasis, in which mast cells are key players. .

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI106874-03
Application #
9171941
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Dong, Gang
Project Start
2014-11-01
Project End
2019-10-31
Budget Start
2016-11-01
Budget End
2017-10-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Wang, Zhenping; Mascarenhas, Nicholas; Eckmann, Lars et al. (2017) Skin microbiome promotes mast cell maturation by triggering stem cell factor production in keratinocytes. J Allergy Clin Immunol 139:1205-1216.e6
Igawa, Satomi; Di Nardo, Anna (2017) Skin microbiome and mast cells. Transl Res 184:68-76
Muto, Yumiko; Wang, Zhenping; Vanderberghe, Matthieu et al. (2014) Mast cells are key mediators of cathelicidin-initiated skin inflammation in rosacea. J Invest Dermatol 134:2728-2736
Roby, Keith D; Nardo, Anna Di (2013) Innate immunity and the role of the antimicrobial peptide cathelicidin in inflammatory skin disease. Drug Discov Today Dis Mech 10:e79-e82
Wang, Zhenping; MacLeod, Daniel T; Di Nardo, Anna (2012) Commensal bacteria lipoteichoic acid increases skin mast cell antimicrobial activity against vaccinia viruses. J Immunol 189:1551-8