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      The role of hypoxic microenvironment in autoimmune diseases

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          Abstract

          The hypoxic microenvironment, characterized by significantly reduced oxygen levels within tissues, has emerged as a critical factor in the pathogenesis and progression of various autoimmune diseases (AIDs). Central to this process is the hypoxia-inducible factor-1 (HIF-1), which orchestrates a wide array of cellular responses under low oxygen conditions. This review delves into the multifaceted roles of the hypoxic microenvironment in modulating immune cell function, particularly highlighting its impact on immune activation, metabolic reprogramming, and angiogenesis. Specific focus is given to the mechanisms by which hypoxia contributes to the development and exacerbation of diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and dermatomyositis (DM). In these conditions, the hypoxic microenvironment not only disrupts immune tolerance but also enhances inflammatory responses and promotes tissue damage. The review also discusses emerging therapeutic strategies aimed at targeting the hypoxic pathways, including the application of HIF-1α inhibitors, mTOR inhibitors, and other modulators of the hypoxic response. By providing a comprehensive overview of the interplay between hypoxia and immune dysfunction in AIDs, this review offers new perspectives on the underlying mechanisms of these diseases and highlights potential avenues for therapeutic intervention.

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          Succinate is an inflammatory signal that induces IL-1β through HIF-1α.

          Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.
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            Rheumatoid arthritis

            Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that primarily affects the joints and is associated with autoantibodies that target various molecules including modified self-epitopes. The identification of novel autoantibodies has improved diagnostic accuracy, and newly developed classification criteria facilitate the recognition and study of the disease early in its course. New clinical assessment tools are able to better characterize disease activity states, which are correlated with progression of damage and disability, and permit improved follow-up. In addition, better understanding of the pathogenesis of RA through recognition of key cells and cytokines has led to the development of targeted disease-modifying antirheumatic drugs. Altogether, the improved understanding of the pathogenetic processes involved, rational use of established drugs and development of new drugs and reliable assessment tools have drastically altered the lives of individuals with RA over the past 2 decades. Current strategies strive for early referral, early diagnosis and early start of effective therapy aimed at remission or, at the least, low disease activity, with rapid adaptation of treatment if this target is not reached. This treat-to-target approach prevents progression of joint damage and optimizes physical functioning, work and social participation. In this Primer, we discuss the epidemiology, pathophysiology, diagnosis and management of RA.
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              Systemic sclerosis.

              Systemic sclerosis, also called scleroderma, is an immune-mediated rheumatic disease that is characterised by fibrosis of the skin and internal organs and vasculopathy. Although systemic sclerosis is uncommon, it has a high morbidity and mortality. Improved understanding of systemic sclerosis has allowed better management of the disease, including improved classification and more systematic assessment and follow-up. Additionally, treatments for specific complications have emerged and a growing evidence base supports the use of immune suppression for the treatment of skin and lung fibrosis. Some manifestations of the disease, such as scleroderma renal crisis, pulmonary arterial hypertension, digital ulceration, and gastro-oesophageal reflux, are now treatable. However, the burden of non-lethal complications associated with systemic sclerosis is substantial and is likely to become more of a challenge. Here, we review the clinical features of systemic sclerosis and describe the best practice approaches for its management. Furthermore, we identify future areas for development.
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                Author and article information

                Contributors
                Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/2742982Role: Role: Role:
                Role: Role:
                URI : https://loop.frontiersin.org/people/672784Role: Role: Role:
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                07 November 2024
                2024
                : 15
                : 1435306
                Affiliations
                [1] 1 Department of Rheumatology and Immunology, Affiliated Hospital of Jiangsu University , Zhenjiang, China
                [2] 2 School of Life Sciences, Jiangsu University , Zhenjiang, China
                Author notes

                Edited by: Mihaela Adriana Ilie, Länssjukhuset i Kalmar, Sweden

                Reviewed by: Luz Pamela Blanco, National Institutes of Health (NIH), United States

                Jairaj Acharya, National Cancer Institute at Frederick (NIH), United States

                Thiruvaimozhi Abimannan, National Cancer Institute at Frederick (NIH), United States, in collaboration with reviewer JA

                *Correspondence: Min Tang, mt3138@ 123456ujs.edu.cn

                †These authors share first authorship

                Article
                10.3389/fimmu.2024.1435306
                11578973
                39575238
                a30833f2-5b4f-4510-b97f-eccce071617d
                Copyright © 2024 Gong, Yang, Wang and Tang

                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
                : 20 May 2024
                : 21 October 2024
                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 273, Pages: 31, Words: 15584
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Science and Technology Plan Projects of Zhenjiang (SH2023078), the Medical Education Collaborative Innovation Fund of Jiangsu University (JDYY2023009) and the National Natural Science Foundation of China (32002235).
                Categories
                Immunology
                Review
                Custom metadata
                Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders

                Immunology
                hypoxic microenvironment,autoimmune diseases,rheumatoid arthritis,hypoxia-inducible factor-1,immune cells

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