Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With M1 Macrophage Polarization in Hidradenitis Suppurativa.
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2021-01
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Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent abscesses, nodules, and sinus tracts in areas of high hair follicle and sweat gland density. These sinus tracts can present with purulent drainage and scar formation. Dysregulation of multiple immune pathways drives the complexity of HS pathogenesis and may account for the heterogeneity of treatment response in HS patients. Using transcriptomic approaches, including single-cell sequencing and protein analysis, we here characterize the innate inflammatory landscape of HS lesions. We identified a shared upregulation of genes involved in interferon (IFN) and antimicrobial defense signaling through transcriptomic overlap analysis of differentially expressed genes (DEGs) in datasets from HS skin, diabetic foot ulcers (DFUs), and the inflammatory stage of normal healing wounds. Overlap analysis between HS- and DFU-specific DEGs revealed an enrichment of gene signatures associated with monocyte/macrophage functions. Single-cell RNA sequencing further revealed monocytes/macrophages with polarization toward a pro-inflammatory M1-like phenotype and increased effector function, including antiviral immunity, phagocytosis, respiratory burst, and antibody-dependent cellular cytotoxicity. Specifically, we identified the STAT1/IFN-signaling axis and the associated IFN-stimulated genes as central players in monocyte/macrophage dysregulation. Our data indicate that monocytes/macrophages are a potential pivotal player in HS pathogenesis and their pathways may serve as therapeutic targets and biomarkers in HS treatment.
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Mariottoni, Paula, Simon W Jiang, Courtney A Prestwood, Vaibhav Jain, Jutamas Suwanpradid, Melodi Javid Whitley, Margaret Coates, David A Brown, et al. (2021). Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With M1 Macrophage Polarization in Hidradenitis Suppurativa. Frontiers in medicine, 8. p. 665873. 10.3389/fmed.2021.665873 Retrieved from https://hdl.handle.net/10161/25654.
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Scholars@Duke
Melodi Javid Whitley
Melodi Javid Whitley, MD, PhD
Assistant Professor of Dermatology
Assistant Program Director for Trainee Research
Director of Transplant Dermatology
I am a physician scientist focused on the dermatologic care of solid organ transplant recipients. Clinically, I manage the the complex dermatologic side effects of immunosuppression with a focus on high-risk skin cancer. My research focuses on understanding the drivers of cutaneous malignancy in this population using translational approaches.
David Andrew Brown
David A. Brown, M.D., Ph.D. is Associate Professor of Surgery and Vice Chief of Research in the Division of Plastic, Maxillofacial, and Oral Surgery at Duke University. Dr. Brown is originally from Colorado and studied engineering at the University of Colorado followed by a Ph.D. in biomedical engineering at UCLA. He subsequently attended medical school at UC Irvine and went on to complete general surgery residency at University of Washington Medical Center followed by plastic surgery residency at Duke University Medical Center. Dr. Brown practices general reconstructive surgery, including the surgical treatment of skin defects resulting from cancer, infection, and trauma. His clinical interests include targeted muscle reinnervation, soft tissue reconstruction of the back, and complex wound healing. He is an NIH-funded researcher exploring mechanisms of limb and digit regeneration in mammals with the hope of one day applying regeneration-based therapies to human diseases. He is the medical director of the Duke Wound Healing Clinic and co-director of the Duke Regeneration Center. Dr. Brown is a Fellow of the American College of Surgeons and is board-certified by the American Board of Surgery, the American Board of Plastic Surgery, and the American Board of Wound Management.
Detlev Erdmann
Simon Gray Gregory
Dr. Gregory is the Margaret Harris and David Silverman Distinguished Professor and Director of the Brain Tumor Omics Program in the Duke Department of Neurosurgery, the Vice Chair of Research in the Department of Neurology, and Director of the Molecular Genomics Core at the Duke Molecular Physiology Institute.
As a neurogenomicist, Dr. Gregory applies the experience gained from leading the sequencing of chromosome 1 for the Human Genome Project to elucidating the mechanisms underlying multi-factorial diseases using genetic, genomic, and epigenetic approaches. Dr. Gregory’s primary areas of research involve understanding the molecular processes associated with disease development and progression in brain tumors and Alzheimer’s disease, drug induced white matter injury repair in multiple sclerosis, and the characterization of lesion microenvironmental changes in MS.
He is broadly regarded across Duke as a leader in the development of novel single cell and spatial molecular technologies towards understanding the pathogenic mechanisms of disease development. Dr. Gregory is also the Section Chair of Genomics and Epigenetics at the DMPI and Director of the Duke Center of Autoimmunity and MS in the Department of Neurology.
Tarannum Jaleel
Jennifer Yunyan Zhang
Epidermis of the skin constitutes the largest organ and the outer most barrier of the body. It is one of the few organs that undergo lifelong self-renewal through a tight balance of cell growth, differentiation, and programmed cell death. Deregulation of this balance is manifested in many diseases, including various immune diseases and cancer.
Our lab is focused on 3 interrelated topics:
1. Gene regulation of epithelial cell proliferation and differentiation
Using regenerated human skin tissues and murine genetic models, we have demonstrated important functions NF-kB and AP-1 gene regulators in epidermal cell growth and differentiation. Currently, our efforts are focused on understating how loss-of-function of CYLD, a deubiquitinase and tumor suppressor, leads to the development of hair follicle defects, skin inflammation, and cancer. Specifically, we want to determine how CYLD integrates NF-kB, AP1, Myc, and other transcription factors to control epidermal cell growth and lineage differentiation.
De novo skin regeneration is life-saving procedure for severely burned patients and lethal genetic skin diseases such as epidermal bullosa. An additional aspect of our study is to improve new skin regeneration techniques and to create experimental skin disease models with gene transduced keratinocytes, as illustrated below.
2. Keratinocytes as instigators of inflammatory responses
Keratinocytes are constantly challenged by external insults, as well as immune cells. Disarray of the crosstalk between keratinocytes and immune cells underlies various immune diseases, including dermatitis, psoriasis, and cutaneous graft-versus-host disease (GVHD). GVHD is a common complication and the leading cause of non-relapse mortality among patients after receiving allogenic hematopoietic stem cell transplantation. The skin is the most commonly affected organ in both the acute and chronic forms of this disease. Treatment options for GVHD are limited and the current standard therapy is high dose systemic corticosteroid which is itself associated with significant morbidity. Our goal is to understand how keratinocytes contribute to the progression of GVHD, and may therefore be targeted to mitigate the disease.
3. Ubiquitination enzymes in melanoma
Melanoma most lethal and difficult to treat skin cancer. In the recent years, BRAF/MEK-targeted therapies have produced exciting results, but they suffer from short duration. Our goal is to uncover novel mechanisms crucial for melanoma malignancy. Specifically, we want to understand how ubiquitination enzymes contribute to melanoma growth. Previously, we have demonstrated that CYLD inhibits melanoma growth through suppression of JNK/AP1 and b1-integrin signaling pathways. In contrast, UBE2N, a K63-Ubiquitin conjusage, promotes melanoma growth in part through activation of the MEK/FRA/SOX10 signaling cascade. Currently, our efforts are focused on understanding how UBE2N and other ubiquitin enzymes regulate the MAPK signaling pathway and whether they can be targeted for melanoma therapy.
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