The multifunctional nature of mast cells (MCs) has been revealed through their involvement in both innate and adaptive immune responses. Recent insight into the various functions of MCs has shown that these innate immune effectors possess the dual ability to kill microbes and to modify classical adaptive immune responses. Members of the cathelicidin family of antimicrobial peptides (AMPs) are expressed by MCs and epithelial cells at sites of injury. The granular localization of the cathelicidin peptides, their extracellular release, and their capacity to modify inflammatory responses suggests that cathelicidin plays an important role in the capacity of MCs to combat skin infection. Preliminary data inside this proposal show that MCs are sentinels in the skin for defending against bacterial and viral infections. Mast cell-deficient (KitW-sash-/-) mice are more susceptible to skin infection than the wild-type mice, while KitW-sash-/- mice reconstituted with skin MCs show a normal response. Using MCs derived from mice deficient in cathelicidin, we showed that antimicrobial peptides (AMPs) are critical anti- pathogenic granule components. Signaling through toll-like receptor (TLR)-2 increased the level of antimicrobial peptide MCs, enhancing their capacity to fight skin infections. The central hypothesis of this proposal is that MCs play a seminal role in the skin innate immune response to infections by orchestrating other cell responses and expressing cathelicidin peptides. Several of the experiments will focus on establishing how MCs modify skin microenvironment and coordinate with other cells to respond to infection (Aim 1). Once the contribution of MCs in skin innate immune defense has been elucidated, Aim 2 will examine the regulation and function of MC AMPs during skin infections. Understanding the role of MCs in skin defense against foreign pathogens will suggest new therapeutic targets for combating infection.
Identifying the contribution of mouse and human mast cell activity in skin innate immune defense will contribute to our understanding of skin infection pathogenesis. Mast cells defend themselves and keep pathogens under control through their ability to produce antimicrobial peptides such as cathelicidins. This proposal will define the innate immune role of skin mast cells in the dermis with the ultimate goal of enhancing their anti-pathogenic activity.
|Choi, Jae Eun; Di Nardo, Anna (2018) Skin neurogenic inflammation. Semin Immunopathol 40:249-259|
|Bernard, Quentin; Wang, Zhenping; Di Nardo, Anna et al. (2017) Interaction of primary mast cells with Borrelia burgdorferi (sensu stricto): role in transmission and dissemination in C57BL/6 mice. Parasit Vectors 10:313|
|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|
|Mascarenhas, Nicholas L; Wang, Zhenping; Chang, Yu-Ling et al. (2017) TRPV4 Mediates Mast Cell Activation in Cathelicidin-Induced Rosacea Inflammation. J Invest Dermatol 137:972-975|
|MacLeod, Daniel T; Nakatsuji, Teruaki; Wang, Zhenping et al. (2015) Vaccinia virus binds to the scavenger receptor MARCO on the surface of keratinocytes. J Invest Dermatol 135:142-150|
|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; Lai, Yuping; Bernard, Jamie J et al. (2012) Skin mast cells protect mice against vaccinia virus by triggering mast cell receptor S1PR2 and releasing antimicrobial peptides. J Immunol 188:345-57|
|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|