The long-term objective of this application is to gain insight into the mechanisms of innate immunity to microbes in skin. The innate immune system must rapidly recognize microbial pathogens and trigger direct host antimicrobial response to limit the infection, yet the activation of the innate immune system also results in inflammation and tissue injury that characterize the clinical manifestations of human disease. This """"""""double- edged sword"""""""" of innate immunity is clearly evident in acne vulgaris in which innate immune cells mount an antimicrobial response to P. acnes, but also induce an inflammatory response mediated by release of cytokines and matrix metalloproteinases (MMPs) that contribute to clinical disease. By investigating the role of the innate immune response in acne, our laboratory has elucidated several novel pathways relevant to clinical disease: i) P. acnes induces the differentiation of monocytes into macrophages with enhanced phagocytosis and antimicrobial activity, ii) P. acnes induces the production of vitamin D receptor-dependent antimicrobial peptide, cathelicidin, in human monocytes, iii) P. acnes induces inflammatory cytokines and MMP9 via toll-like receptor 2-dependent mechanism, iv) all-trans retinoic acid (ATRA) enhances the differentiation of monocytes into CD209+ macrophages and v) ATRA down-regulates TLR2 expression and function by inhibiting P. acnes- induced cytokine production in monocytes. Based on this work, we propose to extend these findings by investigating the differential innate immune responses, antimicrobial vs. inflammatory, to P. acnes in vitro and in vivo. The goal of these studies is to identify mechanistic pathways that differentially regulate the antimicrobial vs. inflammatory responses. It is anticipated that these pathways can be targeted by therapeutic intervention to maximize clinical efficacy while minimizing inflammation and tissue injury in patients with acne. Our proposed experiments should lead to novel avenues of immunologic intervention in acne as well as other cutaneous inflammatory and infectious diseases.

Public Health Relevance

Our application has a significant implication in public health since acne affects the majority of population at some point in their lifetime yet due to limited research in this common skin disease, the pathogenesis is still not clear. In addition, given the restrictions placed on the use of oral retinoids as well as the development of antibiotic- resistant strains of P. acnes, research is needed to improve therapy. Our study will investigate the mechanisms by which P. acnes induces the """"""""double-edged sword"""""""" of the innate immune system, antimicrobial and inflammation, which should provide insight into mechanisms of host defense and tissue injury in skin, leading to novel avenues of immunologic intervention not only in acne but in other cutaneous inflammatory and infectious diseases in general.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Park, Andrew J; Agak, George W; Qin, Min et al. (2017) G2A Attenuates Propionibacterium acnes Induction of Inflammatory Cytokines in Human Monocytes. Ann Dermatol 29:688-698
Yu, Yang; Champer, Jackson; Agak, George W et al. (2016) Different Propionibacterium acnes Phylotypes Induce Distinct Immune Responses and Express Unique Surface and Secreted Proteomes. J Invest Dermatol 136:2221-2228
Hisaw, Lisa D; Qin, Min; Park, Andrew et al. (2016) Antimicrobial Activity of Sebocytes against Propionibacterium acnes via Toll-Like Receptor 2 and Lysosomal Pathway. J Invest Dermatol 136:2098-2101
Yu, Y; Champer, J; Garbán, H et al. (2015) Typing of Propionibacterium acnes: a review of methods and comparative analysis. Br J Dermatol 172:1204-9
Yu, Yang; Champer, Jackson; Kim, Jenny (2015) Analysis of the Surface, Secreted, and Intracellular Proteome of Propionibacterium acnes. EuPA Open Proteom 9:1-7
Qin, Min; Landriscina, Angelo; Rosen, Jamie M et al. (2015) Nitric Oxide-Releasing Nanoparticles Prevent Propionibacterium acnes-Induced Inflammation by Both Clearing the Organism and Inhibiting Microbial Stimulation of the Innate Immune Response. J Invest Dermatol 135:2723-2731
Schmidt, Nathan W; Agak, George W; Deshayes, Stephanie et al. (2015) Pentobra: A Potent Antibiotic with Multiple Layers of Selective Antimicrobial Mechanisms against Propionibacterium Acnes. J Invest Dermatol 135:1581-1589
Agak, George W; Qin, Min; Nobe, Jennifer et al. (2014) Propionibacterium acnes Induces an IL-17 Response in Acne Vulgaris that Is Regulated by Vitamin A and Vitamin D. J Invest Dermatol 134:366-373
Qin, Min; Pirouz, Aslan; Kim, Myung-Hwa et al. (2014) Propionibacterium acnes Induces IL-1? secretion via the NLRP3 inflammasome in human monocytes. J Invest Dermatol 134:381-388
Friedman, Adam J; Phan, Jenny; Schairer, David O et al. (2013) Antimicrobial and anti-inflammatory activity of chitosan-alginate nanoparticles: a targeted therapy for cutaneous pathogens. J Invest Dermatol 133:1231-9

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