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Principal Investigator: Shruti Naik
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $537,321
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
The skin serves as a primary barrier to the external world and is thus often injured. As such, rapid repair
of tissue damage is vital for organismal survival. Failure to repair wounds results in the formation of chronic or
non-healing wounds, which affect over 2% of the western population and cost an estimated 25 billion dollars to
manage annually. Immunosuppression is one major predisposing factor to chronic wound formation, indicating
that signals derived from immune cells are necessary for optimal repair. Yet, there is a significant gap in our
understanding of exactly how immune cells are activated and precisely how they crosstalk with the epithelium to
direct repair.
Normal skin comprises a myriad of “homeostatic” immune cell types that actively patrol the tissue in
health and we find are rapidly activated and recruited to the site of injury. These include type 17 immune cell
subsets that have only been uncovered in the last 10 years and whole function in repair has not been studied in
immunocompetent animals. We systematically ablated each type 17 cell type to determine their role in activating
the wound edge epithelium and found that in type17-γδ T cells, but not other subsets are absolutely necessary
for wound -re-epithelialization. This crosstalk is mediated by the prototypic cytokines IL-17A/F signaling directly
into the epithelium via their receptor IL-17RC. Surprisingly, we uncovered that IL17RC signaling activates HIF1a
protein, and that this signaling axis is required for optimal HIF1a activation at the wound edge even in the pres-
ence of hypoxia. Loss of epithelial HIF1a profoundly disrupts wound re-epithelization indicating that this tran-
scription factor is a master regulator of epithelial activation at the wounds edge. While type17-γδ T cells have
been studied in pathogen responses, how they are recruited and activated in wounds is poorly understood.
Additionally, exactly how IL17 signaling induces HIF1a is unclear and the molecular targets of HIF1a that drive
repair require elucidation.
We will address these fundamental questions in two independent aims: (1) How are type17-γδ T cells
recruited to and activated at the wound’s re-epithelizing front? ; (2) How does inflammatory HIF1a control re-
epithelialization programs downstream of IL-17? Decoding the molecular interactions between wound-associ-
ated lymphocytes and would edge epithelium, as we propose here, is an essential first step in finding immune-
based therapies for chronic non-healing wounds. Moreover, many inflammatory conditions and cancers, driven
by type 17 immunity, co-opt features wound repair. Thus, our studies will not only unearth fundamental mecha-
nisms of immune-epithelial crosstalk in repair, but may also provide novel therapeutic targets for a range of
type17 immunity-mediated epithelial pathologies.
Terms: <Ablation><Activated Lymphocyte><Address><Affect><Animals><Autoimmune><Basal Transcription Factor><Basal transcription factor genes><Binding><Blood Coagulation Factor III><Body Tissues><CD142 Antigens><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Cancerous><Cancers><Cell Anoxia><Cell Body><Cell Communication and Signaling><Cell Hypoxia><Cell Signaling><Cell-Mediated Lympholytic Cells><Cells><Cellular Anoxia><Cellular Hypoxia><Chronic><Coagulation Factor III><Coagulin><Communication><Coupling><Cytokine Signal Transduction><Cytokine Signaling><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Cytotoxic T-Lymphocytes><Data><Dendritic Cells><Dermal><Epithelial Cells><Epithelium><Factor III><Failure><Gamma-delta T cells><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Transcription><Glomerular Procoagulant Activity><Goals><HIF 1><HIF-1 protein><HIF1><HIF1 protein><Health><Hypoxia><Hypoxic><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><Immune><Immune mediated therapy><Immunes><Immunity><Immunocompetent><Immunologically Directed Therapy><Immunologist><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Impaired tissue repair><Impaired wound healing><Impairment><Inflammation><Inflammatory><Injury><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin Receptor><Interleukin-17><Interleukins><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knowledge><Lymphatic cell><Lymphocyte><Lymphocytic><Lymphoid Cell><MHC Receptor><Major Histocompatibility Complex Receptor><Malignant Neoplasms><Malignant Tumor><Maps><Measures><Mediating><Memory><Mice><Mice Mammals><Molecular><Molecular Interaction><Molecular Target><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Oxygen Deficiency><Pathology><Pathway interactions><Population><Position><Positioning Attribute><Predisposing Factor><Production><Proteins><Prothrombinase><RNA Expression><Receptor Protein><Regulatory T-Lymphocyte><Resolution><Risk Factors><Role><Science><Signal Induction><Signal Transduction><Signal Transduction Systems><Signaling><Site><Skin><Specialist><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><Techniques><Technology><Testing><Thromboplastin><Time><Tissue Factor><Tissue Factor Procoagulant><Tissue Thromboplastin><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Treg><Urothromboplastin><Veiled Cells><Wound Repair><abnormal tissue repair><biological signal transduction><cell type><chronic skin wound><chronic wound><cost estimate><cost estimation><cytokine><cytotoxic><delayed wound healing><differential expression><differentially expressed><epithelial injury><epithelial progenitor><epithelial progenitor cell><epithelial stem cell><epithelial wound><healing><hypoxia inducible factor 1><immune competent><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vivo><injured><injuries><injury response><innovate><innovation><innovative><insight><interventional strategy><killer T cell><lymph cell><malignancy><microbial><migration><mouse genetics><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><non-healing wounds><nonhealing wounds><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathogen><pathway><persistent wounds><programs><prototype><re-epithelialization><receptor><recruit><regulatory T-cells><repair><repaired><resolutions><response><response to injury><social role><therapeutic target><thymus derived lymphocyte><tissue repair><tissue wound><transcription factor><transcriptional differences><transcriptomics><wound><wound healing><wound recovery><wound resolution><wounding><wounds><γδ T cells><γδT cells>