|
1
|
Zheng Q, Bao P, Wu X, Zhang X, Huang C, Wang T, Ma C, Zhang M, Chu M, Guo X, Liang C, Pan H, Yan P. Integration of bulk and single-cell RNA sequencing reveals dynamic changes in epidermal cells. Int J Biol Macromol 2025; 309:142601. [PMID: 40158578 DOI: 10.1016/j.ijbiomac.2025.142601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 03/12/2025] [Accepted: 03/26/2025] [Indexed: 04/02/2025]
Abstract
The epidermis and its appendages serve as key systems in stem cell biology. However, despite extensive research, the dynamic changes in these structures and the regulatory mechanisms governing cell behavior during the hair follicle cycle remain incompletely understood. In this study, we employed bulk and single-cell RNA sequencing to investigate the molecular regulation of yak epidermal cell populations across the anagen, catagen, and telogen phases. Through bulk transcriptomics screening, the hub genes potentially involved in the hair follicle cycle of yaks were identified. Single-cell RNA sequencing further revealed the temporal and spatial dynamics of 14 different cell populations in the hair follicle cycle, and reconstructed the trajectory of epidermal cell differentiation. We also found a large overlap of gene modules in the hair follicle microenvironment. Differential gene enrichment analysis of different branches further revealed that the function of hair follicle stem cells is closely related to their spatial location in tissues and their ability to adhere to the basement membrane. Our study not only provides valuable resources for understanding the molecular pathways of the time axis and spatial axis of the hair follicle cycle but is also highly important for future yak breeding.
Collapse
Affiliation(s)
- Qingbo Zheng
- Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China; Institute of Western Agriculture, Chinese Academy of Agricultural Sciences, Changji 831100, China; Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, China
| | - Pengjia Bao
- Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China
| | - Xiaoyun Wu
- Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China
| | - Xiaolan Zhang
- Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China
| | - Chun Huang
- Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China
| | - Tong Wang
- Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China
| | - Chaofan Ma
- Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China
| | - Minghao Zhang
- Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China
| | - Min Chu
- Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China
| | - Xian Guo
- Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China
| | - Chunnian Liang
- Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China
| | - Heping Pan
- Life Science and Engineering College, Northwest Minzu University, Lanzhou 730030, China.
| | - Ping Yan
- Key Laboratory of Animal Genetics and Breeding on Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China; Institute of Western Agriculture, Chinese Academy of Agricultural Sciences, Changji 831100, China; Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, China.
| |
Collapse
|
|
2
|
Fan J, He K, Zhang Y, Li R, Yi X, Li S. HMGB1: new biomarker and therapeutic target of autoimmune and autoinflammatory skin diseases. Front Immunol 2025; 16:1569632. [PMID: 40308590 PMCID: PMC12040678 DOI: 10.3389/fimmu.2025.1569632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Accepted: 03/26/2025] [Indexed: 05/02/2025] Open
Abstract
High-mobility group box 1 (HMGB1) is expressed in almost all human cells. During cell activation and cell death, the nucleoprotein HMGB1 can translocate to the extracellular space, thus mediating the early inflammatory response as an alarmin or damage-associated molecular pattern (DAMP). Extracellular HMGB1 interacts with immune cells by binding to pattern recognition Toll-like receptors (TLRs), including TLR2 and TLR4, and the receptor for advanced glycation end products (RAGE), thus mediating the immune response to protect the host against pathogens and maintain immune balance. HMGB1 is reportedly upregulated and is a critical biomarker for monitoring disease activity in several chronic inflammatory or autoimmune disorders, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus and vitiligo. Additionally, the inhibition of HMGB1 expression or its activity has beneficial effects on disease activity in animal models of autoimmune diseases. Thus, HMGB1 is an indispensable biomarker and an important therapeutic target for autoimmune diseases. This review provides a detailed summary of the biological function of HMGB1 and provides a comprehensive outlook in terms of HMGB-focused diagnostic and therapeutic applications in autoimmune skin diseases.
Collapse
Affiliation(s)
- Jinrong Fan
- The College of Life Sciences, Northwest University, Xi’an, Shaanxi, China
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Kaiqiao He
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yonghui Zhang
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Ruijing Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Xiuli Yi
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Shuli Li
- Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
| |
Collapse
|
|
3
|
Begum S, Hossain MJ, Kim I, Min HS, Lim YN, Cho HJ, Ryu JH. Modulating immune responses in alopecia: therapeutic insights and potential targets of antisense oligonucleotides. BMC Immunol 2025; 26:26. [PMID: 40181256 PMCID: PMC11967052 DOI: 10.1186/s12865-025-00685-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 02/05/2025] [Indexed: 04/05/2025] Open
Abstract
BACKGROUND Alopecia areata (AA) are hair loss disorders with distinct pathogenetic mechanisms involving immune dysregulation and microRNA modulation. AA, a T cell-mediated autoimmune disease, is characterized by sudden hair loss, with interferon-gamma (IFN-γ) playing a pivotal role in pathogenesis. The upregulation of IFN response genes, including IFN-inducible chemokines CXCL9, CXCL10, and CXCL11, in lesional skin reflects the activation of the IFN response pathway and contributes to immune cell recruitment and inflammation. RESULTS Recent research highlights the role of SIRT1, a class III histone deacetylase, in modulating immune responses in AA. SIRT1 inhibition promotes the production of Th1 cytokines and chemokines, impairing inflammation, while SIRT1 activation suppresses autoreactive responses through NF-κB deacetylation and STAT3 phosphorylation. Additionally, antisense oligonucleotides (ASOs) targeting miR-485-3p show therapeutic potential in promoting hair regrowth and mitigating inflammation in murine models of androgenic alopecia (AGA) and AA. CONCLUSION Understanding chemokine dysregulation provides key insights into AA pathogenesis and highlights TAMI-M as a potential therapy for reducing inflammation and promoting hair regeneration. These findings advance the exploration of immune, microRNA, and SIRT1 pathways as targets for novel hair loss treatments.
Collapse
Affiliation(s)
- Shahnaz Begum
- Biorchestra Co. Ltd., (34000) 1, International Science 2-ro, Yuseong-gu, Daejeon (Sindong 658-3), South Korea
| | - Md Jamil Hossain
- Biorchestra Co. Ltd., (34000) 1, International Science 2-ro, Yuseong-gu, Daejeon (Sindong 658-3), South Korea
| | - Insun Kim
- Biorchestra Co. Ltd., (34000) 1, International Science 2-ro, Yuseong-gu, Daejeon (Sindong 658-3), South Korea
| | - Hyun Su Min
- Biorchestra Co. Ltd., (34000) 1, International Science 2-ro, Yuseong-gu, Daejeon (Sindong 658-3), South Korea
| | - Yu Na Lim
- Biorchestra Co. Ltd., (34000) 1, International Science 2-ro, Yuseong-gu, Daejeon (Sindong 658-3), South Korea
| | - Hyun-Jeong Cho
- Department of Biomedical Laboratory Science, College of Medical Science, Konyang University, 158, Gwanjeodong-ro, Seo-gu, Daejeon, 35365, South Korea.
| | - Jin-Hyeob Ryu
- Biorchestra Co. Ltd., (34000) 1, International Science 2-ro, Yuseong-gu, Daejeon (Sindong 658-3), South Korea.
| |
Collapse
|
|
4
|
Lee CB, Šnajdr I, Tenora L, Alt J, Gori S, Krečmerová M, Maragakis RM, Paule J, Tiwari S, Iyer J, Talwar R, Garza L, Majer P, Slusher BS, Rais R. Discovery of Orally Available Prodrugs of Itaconate and Derivatives. J Med Chem 2025; 68:3433-3444. [PMID: 39848624 PMCID: PMC11995693 DOI: 10.1021/acs.jmedchem.4c02646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2025]
Abstract
Itaconate, an endogenous immunomodulator from the tricarboxylic acid (TCA) cycle, shows therapeutic effects in various disease models, but is highly polar with poor cellular permeability. We previously reported a novel, topical itaconate derivative, SCD-153, for the treatment of alopecia areata. Here, we present the discovery of orally available itaconate derivatives for systemic and skin disorders. Four sets of prodrugs were synthesized using pivaloyloxymethyl (POM), isopropyloxycarbonyloxymethyl (POC), (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL), and 3-(hexadecyloxy)propyl (HDP) pro-moieties pairing with itaconic acid (IA), 1-methyl itaconate (1-MI), and 4-methyl itaconate (4-MI). Among these, POC-based prodrugs (P2, P9, P13) showed favorable stability, permeability, and pharmacokinetics. Notably, P2 and P13 significantly inhibited Poly(I:C)/IFNγ-induced inflammatory cytokines in human epidermal keratinocytes. Oral studies demonstrated favorable pharmacokinetics releasing micromolar concentrations of IA or 4-MI from P2 and P13, respectively. These findings highlight the potential of prodrug strategies to enhance itaconate's cellular permeability and oral bioavailability, paving the way for clinical translation.
Collapse
Affiliation(s)
| | - Ivan Šnajdr
- Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Prague 160 00, Czech Republic
| | - Lukáš Tenora
- Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Prague 160 00, Czech Republic
| | | | | | - Marcela Krečmerová
- Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Prague 160 00, Czech Republic
| | | | | | - Sandhya Tiwari
- In Vitro Biology, Sun Pharma Advanced Research Company Ltd., Plot #5 & 6/1, Savli GIDC, Manjusar, Vadodara 391775, Gujarat, India
| | - Jitesh Iyer
- In Vitro Biology, Sun Pharma Advanced Research Company Ltd., Plot #5 & 6/1, Savli GIDC, Manjusar, Vadodara 391775, Gujarat, India
| | - Rashmi Talwar
- In Vitro Biology, Sun Pharma Advanced Research Company Ltd., Plot #5 & 6/1, Savli GIDC, Manjusar, Vadodara 391775, Gujarat, India
| | - Luis Garza
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Pavel Majer
- Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Prague 160 00, Czech Republic
| | | | | |
Collapse
|
|
5
|
Shin JM, Kim KM, Choi MS, Park S, Hong D, Jung KE, Seo YJ, Kim CD, Yang H, Lee Y. The crosstalk between PTEN-induced kinase 1-mediated mitophagy and the inflammasome in the pathogenesis of alopecia areata. Exp Dermatol 2024; 33:e14844. [PMID: 37264692 DOI: 10.1111/exd.14844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 05/18/2023] [Accepted: 05/23/2023] [Indexed: 06/03/2023]
Abstract
Alopecia areata (AA) is a T-cell-mediated autoimmune disease that causes chronic, relapsing hair loss; however, its precise pathogenesis remains to be elucidated. Recent studies have provided compelling evidence of crosstalk between inflammasomes and mitophagy-a process that contributes to the removal of damaged mitochondria. Our previous studies showed that the NLR family pyrin domain containing 3 (NLRP3) inflammasome is important for eliciting and progressing inflammation in AA. In this study, we detected mitochondrial DNA damage in AA-affected scalp tissues and IFNγ and poly(I:C) treated outer root sheath (ORS) cells. In addition, IFNγ and poly(I:C) treatment increased mitochondrial reactive oxygen species (ROS) levels in ORS cells. Moreover, we showed that mitophagy induction alleviates IFNγ and poly(I:C)-induced NLRP3 inflammasome activation in ORS cells. Lastly, PTEN-induced kinase 1 (PINK1) knockdown increased NLRP3 inflammasome activation, indicating that PINK1-mediated mitophagy plays a critical role in NLRP3 inflammasome activation in ORS cells. This study supports previous studies showing that oxidative stress disrupts immune privilege status and promotes autoimmunity in AA. The results emphasize the significance of crosstalk between mitophagy and inflammasomes in the pathogenesis of AA. Finally, mitophagy factors regulating mitochondrial dysfunction and inhibiting inflammasome activation could be novel therapeutic targets for AA.
Collapse
Affiliation(s)
- Jung-Min Shin
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Kyung Min Kim
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Mi Soo Choi
- Department of Dermatology, Dankook University Hospital, Cheonan, Korea
| | - Sanghyun Park
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Dongkyun Hong
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Kyung-Eun Jung
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Young-Joon Seo
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Chang Deok Kim
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Hanseul Yang
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
| | - Young Lee
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| |
Collapse
|
|
6
|
Dainichi T, Iwata M, Kaku Y. Alopecia areata: What's new in the epidemiology, comorbidities, and pathogenesis? J Dermatol Sci 2023; 112:120-127. [PMID: 37833164 DOI: 10.1016/j.jdermsci.2023.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 09/07/2023] [Accepted: 09/29/2023] [Indexed: 10/15/2023]
Abstract
BACKGROUND Alopecia areata (AA) is a common, acquired, and nonscarring type of hair loss that affects people of every generation and is intractable in severe and relapsing cases. Patients with AA, especially those with greater scalp involvement, have poor health-related quality-of-life scores. PURPOSE Following our previous review article in the April 2017 issue of the Journal of Dermatological Science, we aim to provide a pair of review articles on recent progress in multidisciplinary approaches to AA. MAIN FINDINGS We found more than 1800 publications on AA from July 2016 to December 2022. CONCLUSIONS In this review, we focused on the latest information on the epidemiology, comorbidities, and pathogenesis of AA.
Collapse
Affiliation(s)
- Teruki Dainichi
- Department of Dermatology, Kagawa University Faculty of Medicine, Kagawa, Japan.
| | - Masashi Iwata
- Department of Dermatology, Kagawa University Faculty of Medicine, Kagawa, Japan
| | - Yo Kaku
- Department of Dermatology, Kagawa University Faculty of Medicine, Kagawa, Japan; Department of Dermatology, Kurume University School of Medicine, Kurume, Japan
| |
Collapse
|
|
7
|
Fetter T, de Graaf DM, Claus I, Wenzel J. Aberrant inflammasome activation as a driving force of human autoimmune skin disease. Front Immunol 2023; 14:1190388. [PMID: 37325658 PMCID: PMC10266227 DOI: 10.3389/fimmu.2023.1190388] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 05/09/2023] [Indexed: 06/17/2023] Open
Abstract
Autoimmune skin diseases are understood as conditions in which the adaptive immune system with autoantigen-specific T cells and autoantibody-producing B cells reacting against self-tissues plays a crucial pathogenic role. However, there is increasing evidence that inflammasomes, which are large multiprotein complexes that were first described 20 years ago, contribute to autoimmune disease progression. The inflammasome and its contribution to the bioactivation of interleukins IL-1β and IL-18 play an essential role in combating foreign pathogens or tissue damage, but may also act as a pathogenic driver of myriad chronic inflammatory diseases when dysfunctionally regulated. Inflammasomes containing the NOD-like receptor family members NLRP1 and NLRP3 as well as the AIM2-like receptor family member AIM2 have been increasingly investigated in inflammatory skin conditions. In addition to autoinflammatory diseases, which are often associated with skin involvement, the aberrant activation of the inflammasome has also been implied in autoimmune diseases that can either affect the skin besides other organs such as systemic lupus erythematosus and systemic sclerosis or are isolated to the skin in humans. The latter include, among others, the T-cell mediated disorders vitiligo, alopecia areata, lichen planus and cutaneous lupus erythematosus as well as the autoantibody-driven blistering skin disease bullous pemphigoid. Some diseases are characterized by both autoinflammatory and autoimmune responses such as the chronic inflammatory skin disease psoriasis. Further insights into inflammasome dysregulation and associated pathways as well as their role in forming adaptive immune responses in human autoimmune skin pathology could potentially offer a new field of therapeutic options in the future.
Collapse
Affiliation(s)
- Tanja Fetter
- Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany
| | | | - Isabelle Claus
- Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany
| | - Joerg Wenzel
- Department of Dermatology and Allergy, University Hospital Bonn, Bonn, Germany
| |
Collapse
|
|
8
|
Hao L, Nam KH, Lee GJ, Kim D, Shin JM, Lee Y, Kim CD, Kim SJ, Yun SK, Park BH, Park J. SIRT1 downregulation provokes immune-inflammatory responses in hair follicle outer root sheath cells and may contribute to development of alopecia areata. J Dermatol Sci 2023:S0923-1811(23)00126-3. [PMID: 37268558 DOI: 10.1016/j.jdermsci.2023.05.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 05/04/2023] [Accepted: 05/23/2023] [Indexed: 06/04/2023]
Abstract
BACKGROUND Silent information regulator 1 (SIRT1), a type III histone deacetylase, is involved in various cutaneous and systemic autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and psoriasis. However, little is known about the role of SIRT1 in the development of alopecia areata (AA). OBJECTIVES This study investigated whether SIRT1 regulates the hair follicle immune system and is involved in AA pathogenesis. METHODS SIRT1 expression in human scalp tissue was analyzed using immunohistochemical staining, qPCR, and western blotting. The regulatory effect of SIRT1 was evaluated after stimulation with the double-stranded RNA mimic polyinosinic:polycytidylic acid (poly I:C) in hair follicle outer root sheath (ORS) cells and C3H/HeJ mice. RESULTS SIRT1 expression was significantly reduced in the AA scalp compared to the normal scalp. SIRT1 inhibition upregulated MHC class I polypeptide-related sequence A and UL16 binding protein 3 in hair follicle ORS cells. SIRT1 inhibition also promoted the production of Th1 cytokines (IFN-γ and TNF-α), IFN-inducible chemokines (CXCL9 and CXCL10), and T cell migration in ORS cells. Conversely, SIRT1 activation suppressed the autoreactive inflammatory responses. The counteractive effect of the immune response by SIRT1 was mediated through the deacetylation of NF-κB and phosphorylation of STAT3. CONCLUSION SIRT1 downregulation induces immune-inflammatory responses in hair follicle ORS cells and may contribute to AA development.
Collapse
Affiliation(s)
- Lihua Hao
- Department of Dermatology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Kyung-Hwa Nam
- Department of Dermatology, Jeonbuk National University Medical School, Jeonju, the Republic of Korea; Research Institute of Clinical Medicine of Jeonbuk National University and Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, the Republic of Korea
| | - Geon-Jong Lee
- Department of Dermatology, Chungnam National University Medical School, Daejeon, the Republic of Korea
| | - Doyeon Kim
- Department of Dermatology, Chungnam National University Medical School, Daejeon, the Republic of Korea
| | - Jung-Min Shin
- Department of Dermatology, Chungnam National University Medical School, Daejeon, the Republic of Korea
| | - Young Lee
- Department of Dermatology, Chungnam National University Medical School, Daejeon, the Republic of Korea
| | - Chang-Deok Kim
- Department of Dermatology, Chungnam National University Medical School, Daejeon, the Republic of Korea
| | - Seong-Jin Kim
- Department of Dermatology, Chonnam National University Medical School, Kwangju, the Republic of Korea
| | - Seok-Kweon Yun
- Department of Dermatology, Jeonbuk National University Medical School, Jeonju, the Republic of Korea; Research Institute of Clinical Medicine of Jeonbuk National University and Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, the Republic of Korea
| | - Byung-Hyun Park
- Research Institute of Clinical Medicine of Jeonbuk National University and Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, the Republic of Korea; Department of Biochemistry, Jeonbuk National University Medical School, Jeonju, the Republic of Korea
| | - Jin Park
- Department of Dermatology, Jeonbuk National University Medical School, Jeonju, the Republic of Korea; Research Institute of Clinical Medicine of Jeonbuk National University and Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, the Republic of Korea.
| |
Collapse
|
|
9
|
Tsai J, Gori S, Alt J, Tiwari S, Iyer J, Talwar R, Hinsu D, Ahirwar K, Mohanty S, Khunt C, Sutariya B, Jani K, Venkatasubbaiah V, Patel A, Meghapara J, Joshi K, Sahu R, Rana V, Nigade P, Talluri RS, Murty KVSN, Joshi K, Ramanathan V, Li A, Islam N, Snajdr I, Majer P, Rais R, Slusher BS, Garza LA. Topical SCD-153, a 4-methyl itaconate prodrug, for the treatment of alopecia areata. PNAS NEXUS 2023; 2:pgac297. [PMID: 36712931 PMCID: PMC9832969 DOI: 10.1093/pnasnexus/pgac297] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 12/15/2022] [Indexed: 06/18/2023]
Abstract
Alopecia areata is a chronic hair loss disorder that involves autoimmune disruption of hair follicles by CD8+ T cells. Most patients present with patchy hair loss on the scalp that improves spontaneously or with topical and intralesional steroids, topical minoxidil, or topical immunotherapy. However, recurrence of hair loss is common, and patients with extensive disease may require treatment with oral corticosteroids or oral Janus kinase (JAK) inhibitors, both of which may cause systemic toxicities with long-term use. Itaconate is an endogenous molecule synthesized in macrophages that exerts anti-inflammatory effects. To investigate the use of itaconate derivatives for treating alopecia areata, we designed a prodrug of 4-methyl itaconate (4-MI), termed SCD-153, with increased lipophilicity compared to 4-MI (CLogP 1.159 vs. 0.1442) to enhance skin and cell penetration. Topical SCD-153 formed 4-MI upon penetrating the stratum corneum in C57BL/6 mice and showed low systemic absorption. When added to human epidermal keratinocytes stimulated with polyinosinic-polycytidylic acid (poly I:C) or interferon (IFN)γ, SCD-153 significantly attenuated poly I:C-induced interleukin (IL)-6, Toll-like receptor 3, IL-1β, and IFNβ expression, as well as IFNγ-induced IL-6 expression. Topical application of SCD-153 to C57BL/6 mice in the resting (telogen) phase of the hair cycle induced significant hair growth that was statistically superior to vehicle (dimethyl sulfoxide), the less cell-permeable itaconate analogues 4-MI and dimethyl itaconate, and the JAK inhibitor tofacitinib. Our results suggest that SCD-153 is a promising topical candidate for treating alopecia areata.
Collapse
Affiliation(s)
- Jerry Tsai
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Sadakatali Gori
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jesse Alt
- Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Sandhya Tiwari
- In Vitro Biology, Sun Pharma Advanced Research Company, Savli, 391770, India
| | - Jitesh Iyer
- In Vitro Biology, Sun Pharma Advanced Research Company, Savli, 391770, India
| | - Rashmi Talwar
- In Vitro Biology, Sun Pharma Advanced Research Company, Savli, 391770, India
| | - Denish Hinsu
- Preclinical Pharmacology, Sun Pharma Advanced Research Company, Savli, 391770, India
| | - Kailash Ahirwar
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research Ahmedabad, Gandhinagar 382355, India
| | - Swayam Mohanty
- Preclinical Pharmacology, Sun Pharma Advanced Research Company, Savli, 391770, India
| | - Chintan Khunt
- Preclinical Pharmacology, Sun Pharma Advanced Research Company, Savli, 391770, India
| | - Brijesh Sutariya
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, IA 52242, USA
| | - Kaushal Jani
- Preclinical Pharmacology, Sun Pharma Advanced Research Company, Savli, 391770, India
| | | | - Ashok Patel
- Drug Metabolism and Pharmacokinetics, Sun Pharma Advanced Research Company, Savli, 391770, India
| | - Jasmin Meghapara
- Drug Metabolism and Pharmacokinetics, Sun Pharma Advanced Research Company, Savli, 391770, India
| | - Kaushal Joshi
- Drug Metabolism and Pharmacokinetics, Sun Pharma Advanced Research Company, Savli, 391770, India
| | - Rajanikanta Sahu
- Drug Metabolism and Pharmacokinetics, Sun Pharma Advanced Research Company, Savli, 391770, India
| | - Vijay Rana
- Drug Metabolism and Pharmacokinetics, Sun Pharma Advanced Research Company, Savli, 391770, India
| | - Prashant Nigade
- Drug Metabolism and Pharmacokinetics, Sun Pharma Advanced Research Company, Savli, 391770, India
| | - Ravi S Talluri
- Clinical Pharmacology, Sun Pharma Advanced Research Company, Mahakali, Mumbai 400093, India
| | | | - Kiritkumar Joshi
- Medicinal Chemistry, Sun Pharma Advanced Research Company, Savli 391770, India
| | - Vikram Ramanathan
- Translational Development, Sun Pharma Advanced Research Company, Savli 391770, India
| | - Ang Li
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Nasif Islam
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ivan Snajdr
- Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Prague 166 10, Czech Republic
| | - Pavel Majer
- Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Prague 166 10, Czech Republic
| | - Rana Rais
- To whom correspondence should be addressed:
| | | | | |
Collapse
|
|
10
|
Yang JH, Zhao Z, Niu W, Choi HP, Azadzoi KM. Formation of Double Stranded RNA Provokes Smooth Muscle Contractions and Structural Modifications in Bladder Ischemia. Res Rep Urol 2022; 14:399-414. [PMID: 36415310 PMCID: PMC9676006 DOI: 10.2147/rru.s388464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/11/2022] [Indexed: 08/30/2023] Open
Abstract
Purpose Growing evidence suggests that ischemia provokes detrusor overactivity and degenerative responses in the bladder. Underlying mechanisms appear to involve modification of smooth muscle contractile rudiments by hypoxia, redox, cellular stress and cell survival signaling. Downstream pathways of cellular stress and stress response molecules eliciting bladder dysfunction in ischemia remain largely elusive. Our goal was to define the role of double stranded RNA (dsRNA), a stress response molecule provoked by redox, in ischemia mediated bladder dysfunction. Methods A rat model of pelvic ischemia along with a cell culture hypoxia model were used to investigate the expression levels, functional consequences, structural aspects, and regulatory mechanisms of dsRNA in the bladder. Gene and protein expression were examined by reverse transcription polymerase chain reaction (RT-PCR), dot blot, and Western blotting, respectively. Tissue structure and function were assessed using histological staining and organ bath. Regulatory mechanisms were analyzed in cultured bladder smooth muscle cells. Results The data presented here provide the first evidence of the formation of dsRNA in the overactive bladder. dsRNA is a cellular stress response molecule that sensitizes smooth muscle and regulates inflammatory and degenerative rejoinders. Our data suggest that the production of dsRNA in the bladder is provoked by ischemia. Formation of dsRNA appears to augment bladder smooth muscle contractions and provoke fibrotic and apoptotic responses. Downstream actions of dsRNA in the bladder may involve upregulation of dsRNA-activated protein kinase R (PKR) and caspase-3, the executioner of apoptosis. Conclusion Activation of dsRNA/PKR pathway may play a role in sensitization of bladder smooth muscle cells to contractile stimuli, whereas dsRNA and caspase-3 crosstalk appear to modulate cellular stress and instigate degenerative responses in bladder ischemia. These observations suggest the role of dsRNA in bladder dysfunction and may open new perspectives to overcome overactive smooth muscle contractions and structural damage in the bladder.
Collapse
Affiliation(s)
- Jing-Hua Yang
- Department of Surgery, Boston University School of Medicine and Proteomics Laboratory, VA Boston Healthcare System, Boston, MA, USA
| | - Zuohui Zhao
- Department of Urology, Boston University School of Medicine, Boston, MA, USA
| | - Wanting Niu
- Research Department, VA Boston Healthcare System, Boston, MA, USA
| | - Han-Pil Choi
- Research Department, VA Boston Healthcare System, Boston, MA, USA
| | - Kazem M Azadzoi
- Departments of Urology and Pathology, VA Boston Healthcare System and Boston University School of Medicine, Boston, MA, USA
| |
Collapse
|
|
11
|
Shang Y, Yang HX, Li X, Zhang Y, Chen N, Jiang XL, Zhang ZH, Zuo RM, Wang H, Lan XQ, Ren J, Wu YL, Cui ZY, Nan JX, Lian LH. Modulation of IL-36-based inflammatory feedback loop through hepatocytes-derived IL-36R-P2X7R axis improves steatosis in alcoholic steatohepatitis. Br J Pharmacol 2022; 179:4378-4399. [PMID: 35481896 DOI: 10.1111/bph.15858] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 04/02/2022] [Accepted: 04/18/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND AND PURPOSE IL-36 is induced by proinflammatory cytokines and itself promotes inflammatory responses, shaping an IL-36-based inflammation loop. Although, hepatocytes, as "epithelial cell-like" hepatic parenchymal cells, produce IL-36 responses to drug-induced liver injury, little is known about the mechanistic role of the IL-36 signalling during the progression of alcoholic steatohepatitis (ASH). Regarding IL-36/IL-36R and P2X7R coregulates the inflammatory response, we elucidated the modulation of IL-36R-P2X7R-TLRs axis affected hepatocytes steatosis and IL-36-based inflammatory feedback loop that accompanies the onset of ASH. EXPERIMENTAL APPROACH C57BL/6J mice were subjected to chronic-plus-binge ethanol feeding or acute gavage with multiple doses of ethanol to establish ASH, followed by pharmacological inhibition or genetic silencing of IL-36R and P2X7R. AML12 cells or mouse primary hepatocytes were stimulated with alcohol, LPS plus ATP or Poly(I:C) plus ATP, followed by silencing of IL-36γ, IL-36R or P2X7R. KEY RESULTS P2X7R and IL-36R deficiency blocked the inflammatory loop, especially made by IL-36 cytokines, in hepatocytes of mice suffering from ASH. Pharmacological inhibition to P2X7R or IL-36R alleviated lipid accumulation and inflammatory response in ASH. IL-36R was indispensable for P2X7R modulated NLRP3 inflammasome activation in ASH and IL-36 led to a vicious cycle of P2X7R-driven inflammation in alcohol-exposed hepatocytes. TLR ligands promoted IL-36γ production in hepatocytes based on the synergism of P2X7R. CONCLUSIONS AND IMPLICATIONS Blockade of IL-36-based inflammatory feedback loop via IL-36R-P2X7R-TLRs-modulated NLRP3 inflammasome activation circumvented the steatosis and inflammation that accompanies the onset of ASH, suggesting that targeting IL-36 might serve as a novel therapeutic approach to combat ASH.
Collapse
Affiliation(s)
- Yue Shang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission; College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Hong-Xu Yang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission; College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Xia Li
- Department of Pharmacology, Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou Province, China
| | - Yu Zhang
- School of Life Science and Medicine, Shandong University of Technology, Zibo, Shandong Province, China
| | - Nan Chen
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission; College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin Province, China
| | - Xue-Li Jiang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission; College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Zhi-Hong Zhang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission; College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Rong-Mei Zuo
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission; College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Hui Wang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission; College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Xiao-Qi Lan
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission; College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin Province, China
| | - Jie Ren
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission; College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Yan-Ling Wu
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission; College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin Province, China
| | - Zhen-Yu Cui
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission; College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Ji-Xing Nan
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission; College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin Province, China
| | - Li-Hua Lian
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs Commission; College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China.,Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin Province, China
| |
Collapse
|
|
12
|
Kim C, Shin JM, Kim D, Park S, Hong D, Jung KE, Kim CD, Seo YJ, Lee Y. Role of Substance P in Regulating Micro-Milieu of Inflammation in Alopecia Areata. Ann Dermatol 2022; 34:270-277. [PMID: 35948329 PMCID: PMC9365655 DOI: 10.5021/ad.21.161] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 03/10/2022] [Accepted: 03/22/2022] [Indexed: 11/26/2022] Open
Abstract
Background Alopecia areata (AA) is an autoimmune disease characterized by chronic inflammation, the pathogenesis of which is unknown. Stress is believed to play a role; however, evidence remains insufficient. A recent study showed that substance P (SP) damaged hair follicles by causing neurogenic inflammation, activating perifollicular mast cells, and inducing keratinocyte apoptosis. Objective We aimed at studying the role of SP in AA pathogenesis. We investigated the SP levels in the lesional scalp tissues and serum. We also studied the effect of SP on the inflammatory response and hair growth in the outer root sheath (ORS) cells. Methods We compared the serum levels of SP in 58 AA patients and 28 healthy subjects. Then, we checked the expression of SP and SP receptor, neurokinin-1 receptor (NK-1R) in the scalps of AA patients and healthy controls using immunohistochemical staining. Finally, we analyzed the mRNA expression of inflammatory cytokines and hair growth-related factors in ORS cells. Results SP and NK-1R expression were markedly higher in the hair follicles and interfollicular epidermis of the scalp lesions of AA patients. However, there was no statistically significant difference in serum SP levels between controls and patients, regardless of the type of alopecia. SP significantly increased the mRNA expression of inflammatory cytokines and decreased hair growth-related growth factors in ORS cells, but the results were not dramatic. Conclusion SP triggered a localized micro-inflammation in lesional hair follicles, provoked an inflammatory response, and inhibited hair growth, thereby confirming the pathogenic role of SP in AA.
Collapse
Affiliation(s)
- Changhyeon Kim
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Jung-Min Shin
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Doyeon Kim
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Sanghyun Park
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Dongkyun Hong
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Kyung Eun Jung
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Chang-Deok Kim
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Young-Joon Seo
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Young Lee
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| |
Collapse
|
|
13
|
Limbu SL, Purba TS, Harries M, Wikramanayake TC, Miteva M, Bhogal RK, O'Neill CA, Paus R. A folliculocentric perspective of dandruff pathogenesis: Could a troublesome condition be caused by changes to a natural secretory mechanism? Bioessays 2021; 43:e2100005. [PMID: 34486144 DOI: 10.1002/bies.202100005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 07/30/2021] [Accepted: 08/03/2021] [Indexed: 01/19/2023]
Abstract
Dandruff is a common scalp condition, which frequently causes psychological distress in those affected. Dandruff is considered to be caused by an interplay of several factors. However, the pathogenesis of dandruff remains under-investigated, especially with respect to the contribution of the hair follicle. As the hair follicle exhibits unique immune-modulatory properties, including the creation of an immunoinhibitory, immune-privileged milieu, we propose a novel hypothesis taking into account the role of the hair follicle. We hypothesize that the changes and imbalance of yeast and bacterial species, along with increasing proinflammatory sebum by-products, leads to the activation of immune response and inflammation. Hair follicle keratinocytes may then detect these changes in scalp microbiota resulting in the recruitment of leukocytes to the inflammation site. These changes in the scalp skin immune-microenvironment may impact hair follicle immune privilege status, which opens new avenues into exploring the role of the hair follicle in dandruff pathogenesis. Also see the video abstract here: https://youtu.be/mEZEznCYtNs.
Collapse
Affiliation(s)
- Susan L Limbu
- Centre for Dermatology Research, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
| | - Talveen S Purba
- Centre for Dermatology Research, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
| | - Matthew Harries
- Centre for Dermatology Research, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK.,Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Tongyu C Wikramanayake
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Mariya Miteva
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Ranjit K Bhogal
- Unilever R&D Colworth, Colworth Science Park, Sharnbrook, UK
| | - Catherine A O'Neill
- Centre for Dermatology Research, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
| | - Ralf Paus
- Centre for Dermatology Research, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK.,Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.,Monasterium Laboratory, Münster, Germany
| |
Collapse
|
|
14
|
Hashimoto K, Yamada Y, Sekiguchi K, Mori S, Matsumoto T. NLRP3 inflammasome activation contributes to development of alopecia areata in C3H/HeJ mice. Exp Dermatol 2021; 31:133-142. [PMID: 34270818 PMCID: PMC9291919 DOI: 10.1111/exd.14432] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/29/2021] [Accepted: 07/14/2021] [Indexed: 12/31/2022]
Abstract
Alopecia areata (AA) is an autoimmune non‐scarring hair loss disease. Recently, several reports have suggested that innate immune systems such as interferon‐α (IFN‐α)‐producing plasmacytoid dendritic cells and NOD‐like receptor family pyrin domain‐containing protein 3 (NLRP3) inflammasomes play a role in the pathogenesis of AA. However, critical studies about their involvement in the initiation of AA have not yet been reported. Therefore, we investigated the expression of innate immune cytokines in serum and skin, and examined the effect of a selective NLRP3 inhibitor, MCC950, on AA in C3H/HeJ mice, induced by transferring cultured skin‐draining lymph node cells. IFN‐α production was upregulated in lesions of AA‐affected mice, and interleukin‐1β in serum and skin was highly expressed before onset as well as postonset. Furthermore, MCC950 treatment prevented AA development and promoted hair growth in AA mouse models by reducing NLRP3 signalling and Th1/Tc1 chemokines and cytokines in the skin. These results suggest that NLRP3 inflammasome contributes to AA onset and chronicity, and NLRP3 inhibitor may be a potential therapeutic agent for AA.
Collapse
Affiliation(s)
| | | | | | - Sachi Mori
- Kyoto R&D Center, Maruho Co., Ltd., Kyoto, Japan
| | | |
Collapse
|
|
15
|
Lousada MB, Lachnit T, Edelkamp J, Rouillé T, Ajdic D, Uchida Y, Di Nardo A, Bosch TCG, Paus R. Exploring the human hair follicle microbiome. Br J Dermatol 2021; 184:802-815. [PMID: 32762039 DOI: 10.1111/bjd.19461] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/31/2020] [Indexed: 12/31/2022]
Abstract
Human hair follicles (HFs) carry complex microbial communities that differ from the skin surface microbiota. This likely reflects that the HF epithelium differs from the epidermal barrier in that it provides a moist, less acidic, and relatively ultraviolet light-protected environment, part of which is immune-privileged, thus facilitating microbial survival. Here we review the current understanding of the human HF microbiome and its potential physiological and pathological functions, including in folliculitis, acne vulgaris, hidradenitis suppurativa, alopecia areata and cicatricial alopecias. While reviewing the main human HF bacteria (such as Propionibacteria, Corynebacteria, Staphylococci and Streptococci), viruses, fungi and parasites as human HF microbiome constituents, we advocate a broad view of the HF as an integral part of the human holobiont. Specifically, we explore how the human HF may manage its microbiome via the regulated production of antimicrobial peptides (such as cathelicidin, psoriasin, RNAse7 and dermcidin) by HF keratinocytes, how the microbiome may impact on cytokine and chemokine release from the HF, and examine hair growth-modulatory effects of antibiotics, and ask whether the microbiome affects hair growth in turn. We highlight major open questions and potential novel approaches to the management of hair diseases by targeting the HF microbiome.
Collapse
Affiliation(s)
- M B Lousada
- Monasterium Laboratory, Münster, Germany
- Zoological Institute, Christian-Albrechts University Kiel, Kiel, Germany
| | - T Lachnit
- Zoological Institute, Christian-Albrechts University Kiel, Kiel, Germany
| | - J Edelkamp
- Monasterium Laboratory, Münster, Germany
| | - T Rouillé
- Monasterium Laboratory, Münster, Germany
| | - D Ajdic
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Y Uchida
- Monasterium Laboratory, Münster, Germany
| | - A Di Nardo
- Department of Dermatology, University of California, San Diego, CA, USA
| | - T C G Bosch
- Zoological Institute, Christian-Albrechts University Kiel, Kiel, Germany
| | - R Paus
- Monasterium Laboratory, Münster, Germany
- Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
- Centre for Dermatology Research, School of Biological Sciences, University of Manchester & NIHR Biomedical Research Centre, Manchester, UK
| |
Collapse
|
|
16
|
Lee YJ, Park SH, Park HR, Lee Y, Kang H, Kim JE. Mesenchymal Stem Cells Antagonize IFN-Induced Proinflammatory Changes and Growth Inhibition Effects via Wnt/β-Catenin and JAK/STAT Pathway in Human Outer Root Sheath Cells and Hair Follicles. Int J Mol Sci 2021; 22:4581. [PMID: 33925529 PMCID: PMC8123883 DOI: 10.3390/ijms22094581] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/13/2021] [Accepted: 04/22/2021] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stem cell therapy (MSCT) has been shown to be a new therapeutic option for treating alopecia areata (AA). Outer root sheath cells (ORSCs) play key roles in maintaining the hair follicle structure and supporting the bulge area. In human ORSCs (hORSCs), the mechanism for this process has not been extensively studied. In this study, we aimed to examine the influence of human hematopoietic mesenchymal stem cells (hHMSCs) in the hORSCs in vitro model of AA and determine the mechanisms controlling efficacy. Interferon-gamma (IFN-γ) pretreatment was used to induce an in vitro model of AA in hORSCs. The effect of MSCT on the viability and migration of hORSCs was examined using co-cultures, the MTT assay, and migration assays. We investigated the expression of molecules related to the Wnt/β-catenin pathway, JAK/STAT pathway, and growth factors in hHMSC-treated hORSCs by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses. hHMSCs increased hORSC viability and migration when they were co-cultured. hHMSCs reverted IFN-γ-induced expression-including NLRP3, ASC, caspase-1, CXCL-9 through 11, IL-1β, and IL-15-and upregulated several growth factors and hair stem cell markers. hHMSCs activated several molecules in the Wnt/β-catenin signaling pathway, such as in the Wnt families, β-catenin, phosphorylated GSK-3β and cyclin D1, and suppressed the expression of DKK1 induced by IFN-γ in hORSCs. hHMSCs suppressed the phosphorylation of JAK1 to 3, STAT1, and STAT3 compared to the controls and IFN-γ-pretreated hORSCs. These results demonstrate that hHMSCs increased hORSC viability and migration in the in vitro AA model. Additionally, MSCT definitely stimulated anagen survival and hair growth in an HF organ culture model. MSCT appeared to be associated with the Wnt/β-catenin and JAK/STAT pathways in hORSCs.
Collapse
Affiliation(s)
- Yu-Jin Lee
- Department of Dermatology, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Korea; (Y.-J.L.); (S.-H.P.); (H.-R.P.); (H.K.)
| | - Song-Hee Park
- Department of Dermatology, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Korea; (Y.-J.L.); (S.-H.P.); (H.-R.P.); (H.K.)
| | - Hye-Ree Park
- Department of Dermatology, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Korea; (Y.-J.L.); (S.-H.P.); (H.-R.P.); (H.K.)
| | - Young Lee
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon 35015, Korea;
| | - Hoon Kang
- Department of Dermatology, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Korea; (Y.-J.L.); (S.-H.P.); (H.-R.P.); (H.K.)
| | - Jung-Eun Kim
- Department of Dermatology, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Korea; (Y.-J.L.); (S.-H.P.); (H.-R.P.); (H.K.)
| |
Collapse
|
|
17
|
Balık AR, Balık ZB, Aktaş A, Neşelioğlu S, Karabulut E, Karabulut AB. Examination of androgenetic alopecia with serum biomarkers. J Cosmet Dermatol 2020; 20:1855-1859. [PMID: 32969583 DOI: 10.1111/jocd.13732] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 09/11/2020] [Accepted: 09/14/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND Androgenetic alopecia (AGA) is the most common type of hair loss and affects approximately 50% of the male population. AIMS In the present study, to investigate microinflammation, perifollicular fibrosis, and oxidative stress in AGA cases, some serum biomarker levels were measured and evaluated. PATIENTS/METHODS Serum samples were drawn from patients (n = 58) and control (n = 30) groups referring to Atatürk Training and Investigation Hospital Dermatology Outpatient clinic. In serum samples, NF-κB, TNF-α, TGF-β1, thioredoxin, nitric oxide, TOS, TAS, and thiol disulfide homeostasis (native thiol, total thiol, disulfide) were measured and evaluated. RESULTS In patients with AGA, NF-κB (P = .005), TNF-α (P = .008), TGF-β1 (P = .028), thioredoxin (P = .004), nitric oxide (P < .001), and TOS (P < .001) serum levels were found to be significantly higher than those in control group, while TAS (P = .003), native thiol (P < .001), total thiol (P < .001), and disulfide (P < .001) serum levels were found to be significantly lower. CONCLUSIONS According to the results of the present study, it was concluded that in that AGA androgens lead to oxidative stress by increasing free oxygen radicals, which accelerates hair loss by causing microinflammation and fibrosis. The recognition of the effect of androgens and associated factors on the hair follicle cycle is essential for the development of new and effective treatment methods.
Collapse
Affiliation(s)
- Ahmet Rıfat Balık
- Department of Medical Biochemistry, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Zeynep Büşra Balık
- Department of Dermatology, University of Health Sciences Gülhane Training and Investigation Hospital, Ankara, Turkey
| | - Akın Aktaş
- Department of Dermatology, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Salim Neşelioğlu
- Department of Medical Biochemistry, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Ercan Karabulut
- Department of Pharmacology, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Aysun Bay Karabulut
- Department of Medical Biochemistry, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| |
Collapse
|
|
18
|
Szabó IL, Lisztes E, Béke G, Tóth KF, Paus R, Oláh A, Bíró T. The Phytocannabinoid (–)-Cannabidiol Operates as a Complex, Differential Modulator of Human Hair Growth: Anti-Inflammatory Submicromolar versus Hair Growth Inhibitory Micromolar Effects. J Invest Dermatol 2020; 140:484-488.e5. [DOI: 10.1016/j.jid.2019.07.690] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 06/08/2019] [Accepted: 07/02/2019] [Indexed: 12/21/2022]
|
|
19
|
Shin JM, Ko JW, Kwon IS, Choi JW, Hong D, Lee JH, Seo YJ, Kim CD, Lee JH, Lee Y, Park KD. Clinical Relevance for Serum Cold-Inducible RNA-Binding Protein Level in Alopecia Areata. Ann Dermatol 2019; 31:387-392. [PMID: 33911616 PMCID: PMC7992760 DOI: 10.5021/ad.2019.31.4.387] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 12/10/2018] [Accepted: 01/10/2019] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Alopecia areata (AA), a chronic, relapsing hair-loss disorder, is considered to be a T-cell-mediated autoimmune disease. Cold-inducible RNA-binding protein (CIRP) belongs to a family of cold-shock proteins that respond to cold stress, and has been identified as a damage-associated molecular pattern (DAMP) molecule that triggers the inflammatory response. Recent studies have shown that high-mobility group box 1, another DAMP molecule, is elevated in serum and scalp tissue of AA patients, suggesting a relationship between DAMP molecules and the pathogenesis of AA. OBJECTIVE To investigate the clinical significance of serum CIRP levels in AA. METHODS The serum levels of CIRP were compared between 68 patients with AA and 20 healthy controls. Additionally, the correlation between CIRP level and various clinical parameters was evaluated. RESULTS The serum CIRP levels were significantly higher in AA patients compared to healthy subjects. Moreover, there was an association between the serum CIRP level and clinical characteristics, such as disease duration and disease activity. However, there was no significant difference in the serum CIRP level among the clinical types of AA (AA multiplex, alopecia totalis, and alopecia universalis). CONCLUSION These results suggest that CIRP may play a significant role in the pathogenesis of AA and could be a potential biologic marker for monitoring the disease activity of AA.
Collapse
Affiliation(s)
- Jung-Min Shin
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Jung-Woo Ko
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - In Sun Kwon
- Clinical Trials Center, Chungnam National University Hospital, Daejeon, Korea
| | - Jong-Won Choi
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Dongkyun Hong
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Jin-Hyup Lee
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Young-Joon Seo
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Chang-Deok Kim
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Jeung-Hoon Lee
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Young Lee
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Kyung-Duck Park
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| |
Collapse
|
|
20
|
Hwang JH, Chu H, Ahn Y, Kim J, Kim DY. HMGB1 promotes hair growth via the modulation of prostaglandin metabolism. Sci Rep 2019; 9:6660. [PMID: 31040377 PMCID: PMC6491442 DOI: 10.1038/s41598-019-43242-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 04/18/2019] [Indexed: 01/09/2023] Open
Abstract
Unexpected hair growth can occur after tissue injury. The pathogenic mechanism for this phenomenon is unknown but is likely related to inflammatory mediators. One such mediator is high-mobility group box 1 (HMGB1), a ubiquitous nuclear protein that is released from cell nuclei after tissue damage. To elucidate the effect of HMGB1 on hair growth and understand its mechanism of action, we evaluated the effect of HMGB1 treatment on hair shaft elongation and on mRNA and protein expression in cultured human dermal papilla cells (hDPCs). HMGB1 enhanced hair shaft elongation in an ex vivo hair organ culture. In hDPCs, HMGB1 treatment significantly increased mRNA and protein expression levels of prostagladin E synthases. HMGB1 also stimulated prostaglandin E2 (PGE2) secretion from hDPCs. Finally, blocking the receptor for advanced glycation end-products, a canonical HMGB1 receptor, inhibited HMGB1-induced PGE2 production and hair shaft elongation. Our results suggest that HMGB1 promotes hair growth via PGE2 secretion from hDPCs. This mechanism can explain the paradoxical phenomenon of trauma-induced hair growth. Thus, HGMB1 can be a viable therapeutic target for the treatment of alopecia.
Collapse
Affiliation(s)
- Ji-Hye Hwang
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Howard Chu
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Yuri Ahn
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jino Kim
- New Hair Institute, Seoul, Korea
| | - Do-Young Kim
- Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.
| |
Collapse
|
|
21
|
Gong L, Xu XG, Li YH. Embryonic-like regenerative phenomenon: wound-induced hair follicle neogenesis. Regen Med 2018; 13:729-739. [PMID: 30255731 DOI: 10.2217/rme-2018-0028] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Wound-induced hair follicle neogenesis (WIHN) is a regenerative phenomenon that occurs widely in the skin of adult mammalians. A fully functional follicle can regenerate in the center of a full-thickness wound with a large enough size. The cellular origin of this process is similar to embryonic process. Many growth and development-related pathways are involved in WIHN. Studying WIHN can deeply explore the mechanism of biological growth, development and regeneration, and can identify new treatments for hair-related disorders. Our review aims to enlighten future study by summarizing the clinical manifestation of WIHN, as well as the cellular and molecular mechanism of WIHN in recent studies.
Collapse
Affiliation(s)
- Lin Gong
- Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang 110001, PR China
| | - Xue-Gang Xu
- Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang 110001, PR China
| | - Yuan-Hong Li
- Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang 110001, PR China
| |
Collapse
|
|
22
|
Shin JM, Choi DK, Sohn KC, Koh JW, Lee YH, Seo YJ, Kim CD, Lee JH, Lee Y. Induction of alopecia areata in C3H/HeJ mice using polyinosinic-polycytidylic acid (poly[I:C]) and interferon-gamma. Sci Rep 2018; 8:12518. [PMID: 30131581 PMCID: PMC6104095 DOI: 10.1038/s41598-018-30997-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 08/09/2018] [Indexed: 11/09/2022] Open
Abstract
Alopecia areata (AA) is a chronic, relapsing hair-loss disorder that is considered to be a T-cell-mediated autoimmune disease. Several animal models for AA have been created to investigate the pathophysiology and screen for effective therapeutic targets. As C3H/HeJ mice develop AA spontaneously in a low frequency, a novel animal model is needed to establish an AA-like condition faster and more conveniently. In this study, we present a novel non-invasive AA rodent model that avoids skin or lymph-node cell transfer. We simply injected C3H/HeJ mice subcutaneously with interferon-gamma (IFNγ) along with polyinosinic:polycytidylic acid (poly[I:C]), a synthetic dsRNA, to initiate innate immunity via inflammasome activation. Approximately 80% of the IFNγ and poly(I:C) co-injected mice showed patchy AA lesions after 8 weeks. None of the mice displayed hair loss in the IFNγ or poly(I:C) solely injection group. Immunohistochemical staining of the AA lesions revealed increased infiltration of CD4+ and CD8+ cells infiltration around the hair follicles. IFNγ and poly(I:C) increased the expression of NLRP3, IL-1β, CXCL9, CXCL10, and CXCL11 in mouse skin. Taken together, these findings indicate a shorter and more convenient means of AA animal model induction and demonstrate that inflammasome-activated innate immunity is important in AA pathogenesis.
Collapse
Affiliation(s)
- Jung-Min Shin
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Dae-Kyoung Choi
- Biomedical Research Institute, Chungnam National University Hospital, Daejeon, Korea
| | - Kyung-Cheol Sohn
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Jung-Woo Koh
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Young Ho Lee
- Department of Anatomy, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Young-Joon Seo
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Chang Deok Kim
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Jeung-Hoon Lee
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
| | - Young Lee
- Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea.
| |
Collapse
|
|
23
|
Danis J, Janovák L, Gubán B, Göblös A, Szabó K, Kemény L, Bata-Csörgő Z, Széll M. Differential Inflammatory-Response Kinetics of Human Keratinocytes upon Cytosolic RNA- and DNA-Fragment Induction. Int J Mol Sci 2018. [PMID: 29518010 PMCID: PMC5877635 DOI: 10.3390/ijms19030774] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Keratinocytes are non-professional immune cells contributing actively to innate immune responses partially by reacting to a wide range of molecular patterns by activating pattern recognition receptors. Cytosolic nucleotide fragments as pathogen- or self-derived trigger factors are activating inflammasomes and inducing anti-viral signal transduction pathways as well as inducing expression of inflammatory cytokines. We aimed to compare the induced inflammatory reactions in three keratinocyte cell types—normal human epidermal keratinocytes, the HaCaT cell line and the HPV-KER cell line—upon exposure to the synthetic RNA and DNA analogues poly(I:C) and poly(dA:dT) to reveal the underlying signaling events. Both agents induced the expression of interleukin-6 and tumor necrosis factor α in all cell types; however, notable kinetic and expression level differences were found. Western blot analysis revealed rapid activation of the nuclear factor κB (NF-κB), mitogen activated protein kinase and signal transducers of activator of transcription (STAT) signal transduction pathways in keratinocytes upon poly(I:C) treatment, while poly(dA:dT) induced slower activation. Inhibition of NF-κB, p38, STAT-1 and STAT-3 signaling resulted in decreased cytokine expression, whereas inhibition of mitogen-activated protein kinase kinase 1/2 (MEK1/2) signaling showed a negative feedback role in both poly(I:C)- and poly(dA:dT)-induced cytokine expression. Based on our in vitro results nucleotide fragments are able to induce inflammatory reactions in keratinocytes, but with different rate and kinetics of cytokine expression, explained by faster activation of signaling routes by poly(I:C) than poly(dA:dT).
Collapse
Affiliation(s)
- Judit Danis
- Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (L.J.); (B.G.); (A.G.); (L.K.); (Z.B.-C.)
- MTA-SZTE Dermatological Research Group, 6720 Szeged, Hungary; (K.S.); (M.S.)
- Correspondence: ; Tel.: +36-62-54-52-78
| | - Luca Janovák
- Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (L.J.); (B.G.); (A.G.); (L.K.); (Z.B.-C.)
| | - Barbara Gubán
- Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (L.J.); (B.G.); (A.G.); (L.K.); (Z.B.-C.)
| | - Anikó Göblös
- Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (L.J.); (B.G.); (A.G.); (L.K.); (Z.B.-C.)
- MTA-SZTE Dermatological Research Group, 6720 Szeged, Hungary; (K.S.); (M.S.)
| | - Kornélia Szabó
- MTA-SZTE Dermatological Research Group, 6720 Szeged, Hungary; (K.S.); (M.S.)
| | - Lajos Kemény
- Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (L.J.); (B.G.); (A.G.); (L.K.); (Z.B.-C.)
- MTA-SZTE Dermatological Research Group, 6720 Szeged, Hungary; (K.S.); (M.S.)
| | - Zsuzsanna Bata-Csörgő
- Department of Dermatology and Allergology, University of Szeged, 6720 Szeged, Hungary; (L.J.); (B.G.); (A.G.); (L.K.); (Z.B.-C.)
- MTA-SZTE Dermatological Research Group, 6720 Szeged, Hungary; (K.S.); (M.S.)
| | - Márta Széll
- MTA-SZTE Dermatological Research Group, 6720 Szeged, Hungary; (K.S.); (M.S.)
- Department of Medical Genetics, University of Szeged, 6720 Szeged, Hungary
| |
Collapse
|