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Role of Trem1 in ultraviolet radiation-induced immune suppression

Trem1 在紫外线辐射诱导的免疫抑制中的作用

基本信息

批准号：
10434142
负责人：
Hui Xu
金额：
$ 68.09万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-18 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10434142
关键词：
American Cancer Society Animals Antigen-Presenting Cells Blood CD 200 Cancer Patient Cancer Prognosis Cells Cutaneous Data Dendritic Cells Development Diagnosis Disease Environment Epidemic Exposure to Genetic Healthcare Systems Human ITGAM gene Immune Immune response Immunosuppression Incidence Inflammatory Ligands Link Mediating Metals Mus Myeloid Cells Outcome Pathogenesis Peptides Pharmaceutical Preparations Pharmacology Phototherapy Population Prevention Prevention strategy Public Health RNA-Binding Proteins Reaction Regulatory T-Lymphocyte Research Risk Risk Factors Role Signal Transduction Skin Skin Cancer Skin Carcinogenesis Skin Tissue Skin tanning Source Sunlight T-Cell Activation T-Lymphocyte Technology Therapeutic Time UV carcinogenesis UV induced UVB induced Ultraviolet B Radiation Ultraviolet Rays Ultraviolet Therapy United States Welding Work adaptive immunity antagonist antigen-specific T cells base carcinogenesis cell mediated immune response cell type cost draining lymph node extracellular human model mouse model mutant neutrophil novel organ transplant recipient programmed cell death ligand 1 receptor skin organogenesis translational potential tumor ultraviolet

项目摘要

Ultraviolet B (UVB) radiation (290-320 nm) causes immune suppression, in addition to inducing mutant cells. Tumors will occur only when there are mutant cells in an immune suppressive environment. Organ transplant recipients who are treated with immunosuppressive medications have a greatly increased risk (up to 100 times) of UV induced skin cancers and the tumors that do develop behave more aggressively. In the United States, the incidence of skin cancer has doubled from 1992 to 2012. Over 3.5 million new cases are diagnosed each year. The epidemic of skin cancer represents a major public health issue and is a tremendous cost to healthcare systems in the United States and worldwide. It is highly desired to understand the pathogenesis of UVB induced immune suppression and develop new strategies for prevention and treatment. Our preliminary data show that UVB increases Triggering receptor expressed on myeloid cells (Trem)-1 in mouse and human skin tissues and by a portion of CD11b+ cells from the mouse skin and draining lymph nodes. Importantly, we have, for the first time demonstrated that blocking Trem1 with an antagonist peptide inhibits UVB induced immune suppression. Moreover, blocking Trem1 inhibits UVB induced cutaneous carcinogenesis. The findings reveal a previously unrecognized role of Trem1 in UVB induced immune suppression and skin carcinogenesis. Furthermore, a common concept is that UVB induced tolerogenic antigen presenting cells (APC) are required for the induction of immune suppression. Although strong evidence in human and animal studies indicates that CD11b+ cells contain tolerogenic APC, CD11b+ cells are heterogeneous and specific tolerogenic APC remain to be identified. Our data show that UVB induces Trem1 expression by a novel subset of conventional dendritic cell type 2 (cDC2) cells (CD11b+). The UVB induced Trem1+ cDC2 cells in the draining lymph nodes express high levels of immune inhibitory molecules CD200 and PD-L1 and are hardly detectable in normal mice. These findings define novel Trem1+ cDC2 cells and implicate novel mechanisms for Trem1 mediated immune suppression. It forms a strong premise for our hypothesis that UVB induced Trem1+ cDC2 are tolerogenic APC responsible for UVB induced immune suppression and skin carcinogenesis. Targeting Trem1+ cDC2 cells has translational potentials for the prevention and treatment of UVB induced carcinogenesis. Based on the novel findings, proposed studies will examine the hypothesis in animals and humans. Aim 1 will identify UVB induced Trem1+ cDC2 cells as specific tolerogenic APC and determine mechanisms for their immune suppressive activity. Aim 2 will determine mechanisms for the development of UVB induced Trem1+ cDC2 cells. Aim 3 will determine UVB induced Trem1+ cDC2 cells in human skin and blood and determine their roles in immune suppression. Collectively, the current application will apply advanced technology and use genetic and pharmacological approaches to fully characterize the Trem1+ cDC2 cells and explore new mechanisms for UVB induced immune suppression. The outcome will have impacts in the research field and may be exploited to new strategies for prevention and treatment of skin cancers.

紫外线B （UVB）辐射（290-320 nm）除了诱导突变外，还会引起免疫抑制