Dendritic cells (DCs), a heterogeneous population originating from hematopoietic stem cells (HSCs) in the bone marrow (BM), are professional antigen-presenting cells that play key roles in determining the balance between immunity and tolerance induction. Langerhans cells (LCs) are skin-resident DCs that express the C-type lectin Langerin and have a life cycle distinct from many other types of DCs. Even though LCs were first described more than 100 years ago, their development and immunological functions still remain enigmatic. MicroRNAs (miRNAs), a class of 21-25 nt single-stranded non-coding small RNAs, are increasingly being recognized as important regulators of gene expression through the inhibition of effective mRNA translation. The ribonuclease III enzyme Dicer is required for the processing of mature and functional miRNAs. Using Cre-loxP tissue-specific Dicer deletion, our laboratory and others have reported that deletion of miRNAs in HSCs significantly affects the development and function of different immune cells. However, the role of miRNAs in the development of LCs is still currently unknown. To test the roles of miRNAs in the development of LCs, we generated a new mouse strain with tissue- specific disruption of Dicer in LCs using Langerin-Cre. Surprisingly, mice with miRNAs-deficiency in LCs had significantly reduced number of epidermal LCs and the expression of Langerin was significantly reduced in miRNA-deficient LCs. Furthermore, LCs have a specific miRNA gene expression profile compared to other immune cells. Thus, our central hypothesis is that miRNAs are very important components of the molecular circuitry that controls LC development and function. We will test our hypothesis by pursuing the following three Specific Aims: 1) To determine the expression patterns of miRNAs during LC maturation;2) To investigate the role of miRNAs in LC development and function;3) To identify the target genes of miRNAs involved in LC development. Our study will dramatically advance our knowledge on the molecular mechanisms underlying LC development and function, and may also facilitate the development of new intervention strategies for cancer, infectious and autoimmune diseases.

Public Health Relevance

Langerhans cells (LCs) are skin-resident DCs that maintain skin homeostasis, but the detailed molecular pathways regulating LC development and function remain largely unknown. MicroRNAs (miRNAs) are a recently discovered class of evolutionarily conserved small non-coding RNAs that negatively regulate the expression of protein-coding genes. The overall goal of this proposal is to identify the LC-specific miRNA expression profile during development and define their function and direct targets. The results from the above pioneering studies may not only illuminate the new immunological and molecular mechanisms underlying LC development, but may also facilitate the development of new intervention strategies for related autoimmune diseases, infection, and cancer based on the LC cell therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR059976-02
Application #
8131739
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2010-08-19
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$160,651
Indirect Cost
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Wu, Dinghong; Bi, Xinling; Qu, Le et al. (2017) miRNA miR-17-92 cluster is differentially regulated in the imiqumod-treated skin but is not required for imiqumod-induced psoriasis-like dermatitis in mice. Exp Dermatol 26:82-84
Zhang, Xilin; Liu, Queping; Wang, Jie et al. (2016) TIM-4 is differentially expressed in the distinct subsets of dendritic cells in skin and skin-draining lymph nodes and controls skin Langerhans cell homeostasis. Oncotarget 7:37498-37512
Zhang, X; Gu, J; Yu, F-S et al. (2016) TGF-?1-induced transcription factor networks in Langerhans cell development and maintenance. Allergy 71:758-64
Zhou, L; Qi, R-Q; Liu, M et al. (2014) microRNA miR-17-92 cluster is highly expressed in epidermal Langerhans cells but not required for its development. Genes Immun 15:57-61
Mi, Qing-Sheng; Xu, Ying-Ping; Wang, He et al. (2013) Deletion of microRNA miR-223 increases Langerhans cell cross-presentation. Int J Biochem Cell Biol 45:395-400
Xu, Ying-Ping; Qi, Rui-Qun; Chen, Wenbin et al. (2012) Aging affects epidermal Langerhans cell development and function and alters their miRNA gene expression profile. Aging (Albany NY) 4:742-54
Qi, Ruiqun; Liu, Min; Gao, Xing-Hua et al. (2012) Histone deacetylase activity is required for skin Langerhans cell maturation and phagocytosis. J Dermatol Sci 65:152-5
Shi, Yu-Ling; Gu, Jun; Park, Jang-June et al. (2012) Histone deacetylases inhibitor Trichostatin A ameliorates DNFB-induced allergic contact dermatitis and reduces epidermal Langerhans cells in mice. J Dermatol Sci 68:99-107
Xu, Ying-Ping; Shi, Yuling; Cui, Zhi-Zhong et al. (2012) TGF?/Smad3 signal pathway is not required for epidermal Langerhans cell development. J Invest Dermatol 132:2106-9
Zhou, Li; Li, Kai; Shi, Yu-Ling et al. (2012) Systemic analyses of immunophenotypes of peripheral T cells in non-segmental vitiligo: implication of defective natural killer T cells. Pigment Cell Melanoma Res 25:602-11

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