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      Imidazole propionate ameliorates atopic dermatitis-like skin lesions by inhibiting mitochondrial ROS and mTORC2

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          Abstract

          Background

          Imidazole propionate (IMP) is a histidine metabolite produced by some gut microorganisms in the human colon. Increased levels of IMP are associated with intestinal inflammation and the development and progression of cardiovascular disease and diabetes. However, the anti-inflammatory activity of IMP has not been investigated. This study aimed to elucidate the role of IMP in treating atopic dermatitis (AD).

          Methods

          To understand how IMP mediates immunosuppression in AD, IMP was intraperitoneally injected into a Dermatophagoides farinae extract (DFE)/1-chloro-2,4 dinitrochlorobenzene (DNCB)-induced AD-like skin lesions mouse model. We also characterized the anti-inflammatory mechanism of IMP by inducing an AD response in keratinocytes through TNF-α/IFN-γ or IL-4 stimulation.

          Results

          Contrary to the prevailing view that IMP is an unhealthy microbial metabolite, we found that IMP-treated AD-like skin lesions mice showed significant improvement in their clinical symptoms, including ear thickness, epidermal and dermal thickness, and IgE levels. Furthermore, IMP antagonized the expansion of myeloid (neutrophils, macrophages, eosinophils, and mast cells) and Th cells (Th1, Th2, and Th17) in mouse skin and prevented mitochondrial reactive oxygen species production by inhibiting mitochondrial energy production. Interestingly, we found that IMP inhibited AD by reducing glucose uptake in cells to suppress proinflammatory cytokines and chemokines in an AD-like in vitro model, sequentially downregulating the PI3K and mTORC2 signaling pathways centered on Akt, and upregulating DDIT4 and AMPK.

          Discussion

          Our results suggest that IMP exerts anti-inflammatory effects through the metabolic reprogramming of skin inflammation, making it a promising therapeutic candidate for AD and related skin diseases.

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          Most cited references42

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          mTOR signaling in growth control and disease.

          The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation. Copyright © 2012 Elsevier Inc. All rights reserved.
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            A guide to immunometabolism for immunologists.

            In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.
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              Atopic dermatitis.

              Atopic dermatitis is a common inflammatory skin disorder characterised by recurrent eczematous lesions and intense itch. The disorder affects people of all ages and ethnicities, has a substantial psychosocial impact on patients and relatives, and is the leading cause of the global burden from skin disease. Atopic dermatitis is associated with increased risk of multiple comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders. The pathophysiology is complex and involves a strong genetic predisposition, epidermal dysfunction, and T-cell driven inflammation. Although type-2 mechanisms are dominant, there is increasing evidence that the disorder involves multiple immune pathways. Currently, there is no cure, but increasing numbers of innovative and targeted therapies hold promise for achieving disease control, including in patients with recalcitrant disease. We summarise and discuss advances in our understanding of the disease and their implications for prevention, management, and future research.
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                Author and article information

                Contributors
                Role: Role: Role: Role:
                Role: Role: Role: Role:
                Role: Role:
                Role: Role:
                Role: Role:
                URI : https://loop.frontiersin.org/people/1932642Role: Role: Role:
                URI : https://loop.frontiersin.org/people/2007542Role: Role: Role:
                URI : https://loop.frontiersin.org/people/2125302Role: Role: Role: Role: Role: Role: Role:
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                12 March 2024
                2024
                : 15
                : 1324026
                Affiliations
                [1] 1 Department of Immunology, Jeonbuk National University Medical School , Jeonju, Republic of Korea
                [2] 2 Department of Sports Rehabilitation and Exercise Management, University of Gyeongnam Geochang , Geochang-gun, Republic of Korea
                [3] 3 Department of Clinical Pathology, Daegu Health College , Daegu, Republic of Korea
                [4] 4 Department of Physical Education, College of Education, Daegu Catholic University , Gyeongsan, Republic of Korea
                [5] 5 Department of Dermatology, Jeonbuk National University Medical School , Jeonju, Republic of Korea
                [6] 6 Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital , Jeonju, Republic of Korea
                Author notes

                Edited by: Zhenghua Zhang, Fudan University, China

                Reviewed by: Michel Simon, Université de Toulouse, France

                Huijuan Liu, Tianjin International Joint Academy of Biomedicine, China

                *Correspondence: Jin Kyeong Choi, jkchoi@ 123456jbnu.ac.kr

                †These authors have contributed equally to this work

                Article
                10.3389/fimmu.2024.1324026
                10964488
                38533495
                8b33c25b-f322-4360-a9c0-c05a9755d76d
                Copyright © 2024 Kim, Lee, Yoo, Park, Choi, Nam, Park and Choi

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 October 2023
                : 20 February 2024
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 42, Pages: 12, Words: 5876
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by National University Development Project at Jeonbuk National University in 2022.
                Categories
                Immunology
                Original Research
                Custom metadata
                Inflammation

                Immunology
                imidazole propionate,atopic dermatitis,mitochondria ros,mtorc2,ampk,ddit4
                Immunology
                imidazole propionate, atopic dermatitis, mitochondria ros, mtorc2, ampk, ddit4

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