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      Interleukin-17-mediated protective cytokine signaling against degeneration of the retinal pigment epithelium

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          Significance

          Retinal microglia in the subretinal niche have protective functions against injuries to the retinal pigment epithelium (RPE), yet their overactivation can cause neuronal damage. The current research focused on unraveling a signaling network involving choroidal γδ T cells-produced IL-17 (interleukin-17) and RPE-produced IL-6 (interleukin-6). This network was found to be instrumental in metabolically reprogramming subretinal microglia, offering insights into the mechanisms governing their controlled activation.

          Abstract

          Injuries to the retinal pigment epithelium (RPE) and outer retina often result in the accumulation of retinal microglia within the subretinal space. These subretinal microglia play crucial roles in inflammation and resolution, but the mechanisms governing their functions are still largely unknown. Our previous research highlighted the protective functions of choroidal γδ T cells in response to RPE injury. In the current study, we employed single-cell RNA sequencing approach to characterize the profiles of immune cells in mouse choroid. We found that γδ T cells were the primary producer of interleukin-17 (IL-17) in the choroid. IL-17 signaled through its receptor on the RPE, subsequently triggering the production of interleukin-6. This cascade of cytokines initiated a metabolic reprogramming of subretinal microglia, enhancing their capacity for lipid metabolism. RPE-specific knockout of IL-17 receptor A led to the dysfunction of subretinal microglia and RPE pathology. Collectively, our findings suggest that responding to RPE injury, the choroidal γδ T cells can initiate a protective signaling cascade that ensures the proper functioning of subretinal microglia.

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          Most cited references56

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          clusterProfiler 4.0: A universal enrichment tool for interpreting omics data

          Summary Functional enrichment analysis is pivotal for interpreting high-throughput omics data in life science. It is crucial for this type of tool to use the latest annotation databases for as many organisms as possible. To meet these requirements, we present here an updated version of our popular Bioconductor package, clusterProfiler 4.0. This package has been enhanced considerably compared with its original version published 9 years ago. The new version provides a universal interface for functional enrichment analysis in thousands of organisms based on internally supported ontologies and pathways as well as annotation data provided by users or derived from online databases. It also extends the dplyr and ggplot2 packages to offer tidy interfaces for data operation and visualization. Other new features include gene set enrichment analysis and comparison of enrichment results from multiple gene lists. We anticipate that clusterProfiler 4.0 will be applied to a wide range of scenarios across diverse organisms.
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            Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals.

            Gammadelta T cells are an innate source of interleukin-17 (IL-17), preceding the development of the adaptive T helper 17 (Th17) cell response. Here we show that IL-17-producing T cell receptor gammadelta (TCRgammadelta) T cells share characteristic features with Th17 cells, such as expression of chemokine receptor 6 (CCR6), retinoid orphan receptor (RORgammat), aryl hydrocarbon receptor (AhR), and IL-23 receptor. AhR expression in gammadelta T cells was essential for the production of IL-22 but not for optimal IL-17 production. In contrast to Th17 cells, CCR6(+)IL-17-producing gammadelta T cells, but not other gammadelta T cells, express Toll-like receptors TLR1 and TLR2, as well as dectin-1, but not TLR4 and could directly interact with certain pathogens. This process was amplified by IL-23 and resulted in expansion, increased IL-17 production, and recruitment of neutrophils. Thus, innate receptor expression linked with IL-17 production characterizes TCRgammadelta T cells as an efficient first line of defense that can orchestrate an inflammatory response to pathogen-derived as well as environmental signals long before Th17 cells have sensed bacterial invasion.
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              Tuning the Cytokine Responses: An Update on Interleukin (IL)-4 and IL-13 Receptor Complexes

              Interleukin (IL)-4 and IL-13 are related cytokines that regulate many aspects of allergic inflammation. They play important roles in regulating the responses of lymphocytes, myeloid cells, and non-hematopoietic cells. In T-cells, IL-4 induces the differentiation of naïve CD4 T cells into Th2 cells, in B cells, IL-4 drives the immunoglobulin (Ig) class switch to IgG1 and IgE, and in macrophages, IL-4 and IL-13 induce alternative macrophage activation. This review gives a short insight into the functional formation of these cytokine receptors. I will discuss both the binding kinetics of ligand/receptor interactions and the expression of the receptor chains for these cytokines in various cell types; both of which are crucial factors in explaining the efficiency by which these cytokines induce intracellular signaling and gene expression. Work initiated in part by William (Bill) E. Paul on IL-4 some 30 years ago has now grown into a major building block of our current understanding of basic immunology and the immune response. This knowledge on IL-4 has growing clinical importance, as therapeutic approaches targeting the cytokine and its signal transduction are becoming a part of the clinical practice in treating allergic diseases. Just by reading the reference list of this short review, one can appreciate the enormous input Bill has had on shaping our understanding of the pathophysiology of allergic inflammation and in particular the role of IL-4 in this process.
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                Author and article information

                Contributors
                Journal
                Proc Natl Acad Sci U S A
                Proc Natl Acad Sci U S A
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                12 December 2023
                19 December 2023
                12 June 2024
                : 120
                : 51
                : e2311647120
                Affiliations
                [1] aDepartment of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center , Oklahoma City, OK 73104
                [2] bDepartment of Physiology, University of Oklahoma Health Sciences Center , Oklahoma City, OK 73104
                [3] cDepartment of Biochemistry, Wake Forest University School of Medicine , Winston-Salem, NC 27157
                [4] dDepartment of Neurobiology and Anatomy, University of Texas Health Science Center at Houston , Houston, TX 77030
                Author notes
                1To whom correspondence may be addressed. Email: jiyang-cai@ 123456ouhsc.edu .

                Edited by Andrew J. Lotery, University of Southampton, Southampton; received July 9, 2023; accepted November 7, 2023 by Editorial Board Member Jeremy Nathans

                Author information
                https://orcid.org/0000-0001-8451-5498
                https://orcid.org/0009-0001-2419-1062
                https://orcid.org/0000-0003-0938-9078
                https://orcid.org/0000-0003-4755-5452
                Article
                202311647
                10.1073/pnas.2311647120
                10742376
                38085785
                a1872a57-61ec-4f7f-8979-43f96cb1bf47
                Copyright © 2023 the Author(s). Published by PNAS.

                This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                History
                : 09 July 2023
                : 07 November 2023
                Page count
                Pages: 9, Words: 5159
                Funding
                Funded by: HHS | NIH | National Eye Institute (NEI), FundRef 100000053;
                Award ID: EY026999
                Award Recipient : Yan Chen Award Recipient : Sarah E Bounds Award Recipient : Xiang Ma Award Recipient : James Regun Karmoker Award Recipient : Yin Liu Award Recipient : Jian-Xing Ma Award Recipient : Jiyang Cai
                Funded by: HHS | NIH | National Eye Institute (NEI), FundRef 100000053;
                Award ID: EY028773
                Award Recipient : Yan Chen Award Recipient : Sarah E Bounds Award Recipient : Xiang Ma Award Recipient : James Regun Karmoker Award Recipient : Yin Liu Award Recipient : Jian-Xing Ma Award Recipient : Jiyang Cai
                Funded by: HHS | NIH | National Eye Institute (NEI), FundRef 100000053;
                Award ID: EY034510
                Award Recipient : Yan Chen Award Recipient : Sarah E Bounds Award Recipient : Xiang Ma Award Recipient : James Regun Karmoker Award Recipient : Yin Liu Award Recipient : Jian-Xing Ma Award Recipient : Jiyang Cai
                Funded by: HHS | NIH | National Eye Institute (NEI), FundRef 100000053;
                Award ID: EY028949
                Award Recipient : Yan Chen Award Recipient : Sarah E Bounds Award Recipient : Xiang Ma Award Recipient : James Regun Karmoker Award Recipient : Yin Liu Award Recipient : Jian-Xing Ma Award Recipient : Jiyang Cai
                Funded by: HHS | NIH | National Eye Institute (NEI), FundRef 100000053;
                Award ID: EY027125
                Award Recipient : Yan Chen Award Recipient : Sarah E Bounds Award Recipient : Xiang Ma Award Recipient : James Regun Karmoker Award Recipient : Yin Liu Award Recipient : Jian-Xing Ma Award Recipient : Jiyang Cai
                Funded by: BrightFocus Foundation (BFF), FundRef 100006312;
                Award ID: M2017186
                Award Recipient : Yan Chen
                Funded by: Presbyterian Health Foundation (PHF), FundRef 100001298;
                Award ID: 20222421
                Award Recipient : Yan Chen
                Funded by: Presbyterian Health Foundation (PHF), FundRef 100001298;
                Award ID: 20221626
                Award Recipient : Yan Chen
                Funded by: HHS | NIH | National Eye Institute (NEI), FundRef 100000053;
                Award ID: EY034742
                Award Recipient : Yan Chen Award Recipient : Sarah E Bounds Award Recipient : Xiang Ma Award Recipient : James Regun Karmoker Award Recipient : Yin Liu Award Recipient : Jian-Xing Ma Award Recipient : Jiyang Cai
                Categories
                research-article, Research Article
                cell-bio, Cell Biology
                409
                Biological Sciences
                Cell Biology

                age-related macular degeneration,microglia,cytokine
                age-related macular degeneration, microglia, cytokine

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