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Lyu P, Wen J, Zhang W, Liu N, Stolzer I, Gießl A, Jia Y, Mauro D, Zhang F, Ciccia F, Soulat D, Günther C, Schett G, Bozec A. Expression of HIF1α in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery. Ann Rheum Dis 2024; 83:984-997. [PMID: 38503474 PMCID: PMC11287550 DOI: 10.1136/ard-2023-224491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 02/28/2024] [Indexed: 03/21/2024]
Abstract
OBJECTIVES To investigate the mechanism by which intestinal epithelial cell (IEC) death induces arthritis. METHODS IEC death was assessed by staining for necroptosis and apoptosis markers and fluorescence in situ hybridisation at different time points during collagen-induced arthritis (CIA). During the development of CIA, messenger RNA (mRNA) sequencing was performed, followed by Gene Ontology enrichment analysis of differentially expressed genes. Mice deficient for hypoxia-inducible factor 1α (Hif1a) in IECs (Hif1a ∆IEC) were generated and induced for arthritis. mRNA sequencing, chromatin immunoprecipitated (ChIP) DNA sequencing and ChIP-qualitative PCR were performed on IECs from Hif1a ∆IEC mice and littermate controls. Effects of HIF1α stabilisation by inhibition of prolyl hydroxylase domain-containing enzymes and treatment with the inhibitor of receptor-interacting protein kinase-3 (RIPK3) were tested in intestinal organoids and in CIA. RESULTS IEC underwent apoptotic and necroptotic cell death at the onset of arthritis, leading to impaired gut barrier function. HIF1α was identified as one of the most upregulated genes in IECs during the onset of arthritis. Deletion of Hif1a in IEC enhanced IEC necroptosis, triggered intestinal inflammation and exacerbated arthritis. HIF1α was found to be a key transcriptional repressor for the necroptosis-inducing factor RIPK3. Enhanced RIPK3 expression, indicating necroptosis, was also found in the intestinal epithelium of patients with new-onset rheumatoid arthritis. Therapeutic stabilisation of HIF1α as well as small-molecule-based RIPK3 inhibition rescued intestinal necroptosis in vitro and in vivo and suppressed the development of arthritis. CONCLUSION Our results identify IEC necroptosis as a critical link between the gut and the development of arthritis.
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Affiliation(s)
- Pang Lyu
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Jinming Wen
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Wenshuo Zhang
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Ning Liu
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Iris Stolzer
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Department of Internal Medicine 1, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany
| | - Andreas Gießl
- Department of Opthalmology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Yewei Jia
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Daniele Mauro
- Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy
| | - Fulin Zhang
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Francesco Ciccia
- Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Campania, Italy
| | - Didier Soulat
- Microbiology Institute, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Claudia Günther
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Department of Internal Medicine 1, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Bayern, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Aline Bozec
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
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Xiao J, Guo X, Wang Z. Crosstalk between hypoxia-inducible factor-1α and short-chain fatty acids in inflammatory bowel disease: key clues toward unraveling the mystery. Front Immunol 2024; 15:1385907. [PMID: 38605960 PMCID: PMC11007100 DOI: 10.3389/fimmu.2024.1385907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 03/19/2024] [Indexed: 04/13/2024] Open
Abstract
The human intestinal tract constitutes a complex ecosystem, made up of countless gut microbiota, metabolites, and immune cells, with hypoxia being a fundamental environmental characteristic of this ecology. Under normal physiological conditions, a delicate balance exists among these complex "residents", with disruptions potentially leading to inflammatory bowel disease (IBD). The core pathology of IBD features a disrupted intestinal epithelial barrier, alongside evident immune and microecological disturbances. Central to these interconnected networks is hypoxia-inducible factor-1α (HIF-1α), which is a key regulator in gut cells for adapting to hypoxic conditions and maintaining gut homeostasis. Short-chain fatty acids (SCFAs), as pivotal gut metabolites, serve as vital mediators between the host and microbiota, and significantly influence intestinal ecosystem. Recent years have seen a surge in research on the roles and therapeutic potential of HIF-1α and SCFAs in IBD independently, yet reviews on HIF-1α-mediated SCFAs regulation of IBD under hypoxic conditions are scarce. This article summarizes evidence of the interplay and regulatory relationship between SCFAs and HIF-1α in IBD, pivotal for elucidating the disease's pathogenesis and offering promising therapeutic strategies.
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Affiliation(s)
- Jinyin Xiao
- Graduate School, Hunan University of Traditional Chinese Medicine, Changsha, China
- Department of Anorectal, the Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha, China
| | - Xiajun Guo
- Department of Geriatric, the First People’s Hospital of Xiangtan City, Xiangtan, China
| | - Zhenquan Wang
- Department of Anorectal, the Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha, China
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Yuan X, Ruan W, Bobrow B, Carmeliet P, Eltzschig HK. Targeting hypoxia-inducible factors: therapeutic opportunities and challenges. Nat Rev Drug Discov 2024; 23:175-200. [PMID: 38123660 DOI: 10.1038/s41573-023-00848-6] [Citation(s) in RCA: 52] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2023] [Indexed: 12/23/2023]
Abstract
Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that are crucial for adaptation of metazoans to limited oxygen availability. Recently, HIF activation and inhibition have emerged as therapeutic targets in various human diseases. Pharmacologically desirable effects of HIF activation include erythropoiesis stimulation, cellular metabolism optimization during hypoxia and adaptive responses during ischaemia and inflammation. By contrast, HIF inhibition has been explored as a therapy for various cancers, retinal neovascularization and pulmonary hypertension. This Review discusses the biochemical mechanisms that control HIF stabilization and the molecular strategies that can be exploited pharmacologically to activate or inhibit HIFs. In addition, we examine medical conditions that benefit from targeting HIFs, the potential side effects of HIF activation or inhibition and future challenges in this field.
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Affiliation(s)
- Xiaoyi Yuan
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
| | - Wei Ruan
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Department of Anaesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bentley Bobrow
- Department of Emergency Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Peter Carmeliet
- Laboratory of Angiogenesis & Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, KU Leuven, Leuven, Belgium
- Laboratory of Angiogenesis & Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Holger K Eltzschig
- Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
- Outcomes Research Consortium, Cleveland, OH, USA.
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Xu Y, Sa Y, Zhang C, Wang J, Shao Q, Liu J, Wang S, Zhou J. A preventative role of nitrate for hypoxia-induced intestinal injury. Free Radic Biol Med 2024; 213:457-469. [PMID: 38281627 DOI: 10.1016/j.freeradbiomed.2024.01.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 01/02/2024] [Accepted: 01/18/2024] [Indexed: 01/30/2024]
Abstract
BACKGROUND Studying effective interventions for hypoxia-induced injury is crucial, particularly in high-altitude areas. Symptoms stemming from intestinal injuries have a significant impact on the health of individuals transitioning from plains to plateau regions. This research explores the effects and mechanisms of nitrate supplementation in preventing hypoxia-induced intestinal injury. METHODS A hypoxia survival mouse model was established using 7% O2 conditions. The intervention with 4 mM sodium nitrate (NaNO3) in drinking water commenced 7 days prior to hypoxia exposure. Weight monitoring, hematoxylin and eosin (HE) staining, transmission electron microscopy (TEM), and intestinal permeability assays were employed for physiological, histological, and functional analyses. Quantitative PCR (qPCR), Western blot, and immunofluorescence were utilized to analyze the levels of tight junction (TJ) proteins and hypoxia-inducible factor 1α (Hif 1α). RNA sequencing (RNA-seq) identified nitrate's target, and chromatin immunoprecipitation (ChIP) verified the transcriptional impact of Hif 1α on TJ proteins. Villin-cre mice infected with AAV9-FLEX-EGFP-Hif 1α were used for mechanism validation. RESULTS The results demonstrated that nitrate supplementation significantly alleviated small intestinal epithelial cell necrosis, intestinal permeability, disruption of TJs, and weight loss under hypoxia. Moreover, the nitrate-triggered enhancement of TJs is mediated by Hif 1α nuclear translocation and its subsequent transcriptional function. The effect of nitrate supplementation on TJs was largely attributed to the stimulation of the EGFR/PI3K/AKT/mTOR/Hif 1α signaling pathways. CONCLUSION Nitrate serves as a novel approach in preventing hypoxia-induced intestinal injury, acting through Hif 1α activation to promote the transcription of TJ proteins. Furthermore, our study provides new and compelling evidence for the protective effects of nitrate in hypoxic conditions, especially at high altitudes.
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Affiliation(s)
- Yifan Xu
- Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing China
| | - Yunqiong Sa
- Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing China
| | - Chunmei Zhang
- Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing China; Laboratory for Oral and General Health Integration and Translation, Beijing Tiantan Hospital, Capital Medical University, Beijing China
| | - Jinsong Wang
- Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing China
| | - Qianqian Shao
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Beijing Advanced Innovation Center for Big Data-based Precision Medicine, Capital Medical University, Beijing, China
| | - Jia Liu
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Beijing Advanced Innovation Center for Big Data-based Precision Medicine, Capital Medical University, Beijing, China
| | - Songlin Wang
- Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing China; Immunology Research Centre for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing China; Laboratory for Oral and General Health Integration and Translation, Beijing Tiantan Hospital, Capital Medical University, Beijing China; Research Units of Tooth Development and Regeneration, Chinese Academy of Medical Sciences, Beijing China.
| | - Jian Zhou
- Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health and Beijing Stomatological Hospital, Capital Medical University, Beijing, China; Immunology Research Centre for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing China; Laboratory for Oral and General Health Integration and Translation, Beijing Tiantan Hospital, Capital Medical University, Beijing China; Department of VIP Dental Service, School of Stomatology, Capital Medical University, Beijing, 100050, China.
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Cheng J, Sun Y, Zhao Y, Guo Q, Wang Z, Wang R. Research Progress on the Mechanism of Intestinal Barrier Damage and Drug Therapy in a High Altitude Environment. Curr Drug Deliv 2024; 21:807-816. [PMID: 36892115 DOI: 10.2174/1567201820666230309090241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 01/13/2023] [Accepted: 01/23/2023] [Indexed: 03/10/2023]
Abstract
The plateau is a typical extreme environment with low temperature, low oxygen and high ultraviolet rays. The integrity of the intestinal barrier is the basis for the functioning of the intestine, which plays an important role in absorbing nutrients, maintaining the balance of intestinal flora, and blocking the invasion of toxins. Currently, there is increasing evidence that high altitude environment can enhance intestinal permeability and disrupt intestinal barrier integrity. This article mainly focuses on the regulation of the expression of HIF and tight junction proteins in the high altitude environment, which promotes the release of pro-inflammatory factors, especially the imbalance of intestinal flora caused by the high altitude environment. The mechanism of intestinal barrier damage and the drugs to protect the intestinal barrier are reviewed. Studying the mechanism of intestinal barrier damage in high altitude environment is not only conducive to understanding the mechanism of high altitude environment affecting intestinal barrier function, but also provides a more scientific medicine treatment method for intestinal damage caused by the special high altitude environment.
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Affiliation(s)
- Junfei Cheng
- PLA Key Laboratory of Plateau Environmental Damage Control, Lanzhou General Hospital of Lanzhou Military Command, Lanzhou, 730050, China
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Yuemei Sun
- PLA Key Laboratory of Plateau Environmental Damage Control, Lanzhou General Hospital of Lanzhou Military Command, Lanzhou, 730050, China
| | - Yilan Zhao
- PLA Key Laboratory of Plateau Environmental Damage Control, Lanzhou General Hospital of Lanzhou Military Command, Lanzhou, 730050, China
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
| | - Qianwen Guo
- PLA Key Laboratory of Plateau Environmental Damage Control, Lanzhou General Hospital of Lanzhou Military Command, Lanzhou, 730050, China
| | - ZiHan Wang
- PLA Key Laboratory of Plateau Environmental Damage Control, Lanzhou General Hospital of Lanzhou Military Command, Lanzhou, 730050, China
| | - Rong Wang
- PLA Key Laboratory of Plateau Environmental Damage Control, Lanzhou General Hospital of Lanzhou Military Command, Lanzhou, 730050, China
- School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
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Ornelas A, Welch N, Countess JA, Zhou L, Wang RX, Dowdell AS, Colgan SP. Mimicry of microbially-derived butyrate reveals templates for potent intestinal epithelial HIF stabilizers. Gut Microbes 2023; 15:2267706. [PMID: 37822087 PMCID: PMC10572066 DOI: 10.1080/19490976.2023.2267706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 10/03/2023] [Indexed: 10/13/2023] Open
Abstract
Microbiota-derived short-chain fatty acids, including butyrate (BA), have multiple beneficial health effects. In the colon, BA concentrations range from 10 to 20 mM and up to 95% is utilized as energy by the mucosa. BA plays a key role in epithelial-barrier regulation and anti-inflammation, and regulates cell growth and differentiation, at least in part, due to its direct influence on stabilization of the transcription factor hypoxia-inducible factor (HIF). It remains unclear whether BA is the optimal metabolite for such a response. In this study, we explored metabolite mimicry as an attractive strategy for the biological response to HIF. We discovered that 4-mercapto butyrate (MBA) stabilizes HIF more potently and has a longer biological half-life than BA in intestinal epithelial cells (IECs). We validated the MBA-mediated HIF transcriptional activity through the induction of classic HIF gene targets in IECs and enhanced epithelial barrier formation in vitro. In-vivo studies with MBA revealed systemic HIF stabilization in mice, which was more potent than its parent BA metabolite. Mechanistically, we found that MBA enhances oxygen consumption and that the sulfhydryl group is essential for HIF stabilization, but exclusively as a four-carbon SCFA. These findings reveal a combined biochemical mechanism for HIF stabilization and provide a foundation for the discovery of potent metabolite-like scaffolds.
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Affiliation(s)
- Alfredo Ornelas
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, University of Colorado, Aurora, CO, USA
| | - Nichole Welch
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, University of Colorado, Aurora, CO, USA
- Department of Medicine, Rocky Mountain Veterans Association, Aurora, CO, USA
| | - Jacob A. Countess
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, University of Colorado, Aurora, CO, USA
| | - Liheng Zhou
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, University of Colorado, Aurora, CO, USA
| | - Ruth X. Wang
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, University of Colorado, Aurora, CO, USA
| | - Alexander S. Dowdell
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, University of Colorado, Aurora, CO, USA
- Department of Medicine, Rocky Mountain Veterans Association, Aurora, CO, USA
| | - Sean P. Colgan
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, University of Colorado, Aurora, CO, USA
- Department of Medicine, Rocky Mountain Veterans Association, Aurora, CO, USA
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Zhi X, Shi S, Li Y, Ma M, Long Y, Li C, Hao H, Liu H, Wang X, Wang L. S100a9 inhibits Atg9a transcription and participates in suppression of autophagy in cardiomyocytes induced by β 1-adrenoceptor autoantibodies. Cell Mol Biol Lett 2023; 28:74. [PMID: 37723445 PMCID: PMC10506287 DOI: 10.1186/s11658-023-00486-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 08/31/2023] [Indexed: 09/20/2023] Open
Abstract
BACKGROUND Cardiomyocyte death induced by autophagy inhibition is an important cause of cardiac dysfunction. In-depth exploration of its mechanism may help to improve cardiac dysfunction. In our previous study, we found that β1-adrenergic receptor autoantibodies (β1-AAs) induced a decrease in myocardial autophagy and caused cardiomyocyte death, thus resulting in cardiac dysfunction. Through tandem mass tag (TMT)-based quantitative proteomics, autophagy-related S100a9 protein was found to be significantly upregulated in the myocardial tissue of actively immunized mice. However, whether S100a9 affects the cardiac function in the presence of β1-AAs through autophagy and the specific mechanism are currently unclear. METHODS In this study, the active immunity method was used to establish a β1-AA-induced mouse cardiac dysfunction model, and RT-PCR and western blot were used to detect changes in gene and protein expression in cardiomyocytes. We used siRNA to knockdown S100a9 in cardiomyocytes. An autophagy PCR array was performed to screen differentially expressed autophagy-related genes in cells transfected with S100a9 siRNA and negative control siRNA. Cytoplasmic nuclear separation, co-immunoprecipitation (Co-IP), and immunofluorescence were used to detect the binding of S100a9 and hypoxia inducible factor-1α (HIF-1α). Finally, AAV9-S100a9-RNAi was injected into mice via the tail vein to knockdown S100a9 in cardiomyocytes. Cardiac function was detected via ultrasonography. RESULTS The results showed that β1-AAs induced S100a9 expression. The PCR array indicated that Atg9a changed significantly in S100a9siRNA cells and that β1-AAs increased the binding of S100a9 and HIF-1α in cytoplasm. Knockdown of S100a9 significantly improved autophagy levels and cardiac dysfunction. CONCLUSION Our research showed that β1-AAs increased S100a9 expression in cardiomyocytes and that S100a9 interacted with HIF-1α, which prevented HIF-1α from entering the nucleus normally, thus inhibiting the transcription of Atg9a. This resulted in autophagy inhibition and cardiac dysfunction.
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Affiliation(s)
- Xiaoyan Zhi
- Department of Pathology, Shanxi Medical University, No.56 Xinjian South Road, Taiyuan, Shanxi, 030001, People's Republic of China
| | - Shu Shi
- Department of Pathology, Shanxi Medical University, No.56 Xinjian South Road, Taiyuan, Shanxi, 030001, People's Republic of China
| | - Yang Li
- Department of Pathology, Shanxi Medical University, No.56 Xinjian South Road, Taiyuan, Shanxi, 030001, People's Republic of China
| | - Mingxia Ma
- Department of Pathology, Shanxi Medical University, No.56 Xinjian South Road, Taiyuan, Shanxi, 030001, People's Republic of China
| | - Yaolin Long
- Department of Pathology, Shanxi Medical University, No.56 Xinjian South Road, Taiyuan, Shanxi, 030001, People's Republic of China
| | - Chen Li
- Department of Pathology, Shanxi Medical University, No.56 Xinjian South Road, Taiyuan, Shanxi, 030001, People's Republic of China
| | - Haihu Hao
- Department of Orthopaedics, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, People's Republic of China
| | - Huirong Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, People's Republic of China
| | - Xiaohui Wang
- Department of Pathology, Shanxi Medical University, No.56 Xinjian South Road, Taiyuan, Shanxi, 030001, People's Republic of China
| | - Li Wang
- Department of Pathology, Shanxi Medical University, No.56 Xinjian South Road, Taiyuan, Shanxi, 030001, People's Republic of China.
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Ruan W, Eltzschig HK, Yuan X. Hypoxia-stabilized RIPK1 promotes cell death. Nat Cell Biol 2023:10.1038/s41556-023-01176-y. [PMID: 37400499 DOI: 10.1038/s41556-023-01176-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/05/2023]
Affiliation(s)
- Wei Ruan
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Holger K Eltzschig
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Outcomes Research Consortium, Cleveland, OH, USA
| | - Xiaoyi Yuan
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
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DeMichele E, Sosnowski O, Buret AG, Allain T. Regulatory Functions of Hypoxia in Host-Parasite Interactions: A Focus on Enteric, Tissue, and Blood Protozoa. Microorganisms 2023; 11:1598. [PMID: 37375100 PMCID: PMC10303274 DOI: 10.3390/microorganisms11061598] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Body tissues are subjected to various oxygenic gradients and fluctuations and hence can become transiently hypoxic. Hypoxia-inducible factor (HIF) is the master transcriptional regulator of the cellular hypoxic response and is capable of modulating cellular metabolism, immune responses, epithelial barrier integrity, and local microbiota. Recent reports have characterized the hypoxic response to various infections. However, little is known about the role of HIF activation in the context of protozoan parasitic infections. Growing evidence suggests that tissue and blood protozoa can activate HIF and subsequent HIF target genes in the host, helping or hindering their pathogenicity. In the gut, enteric protozoa are adapted to steep longitudinal and radial oxygen gradients to complete their life cycle, yet the role of HIF during these protozoan infections remains unclear. This review focuses on the hypoxic response to protozoa and its role in the pathophysiology of parasitic infections. We also discuss how hypoxia modulates host immune responses in the context of protozoan infections.
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Affiliation(s)
- Emily DeMichele
- Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada; (E.D.); (O.S.); (A.G.B.)
- Inflammation Research Network, University of Calgary, Calgary, AB T2N 1N4, Canada
- Host-Parasite Interactions, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Olivia Sosnowski
- Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada; (E.D.); (O.S.); (A.G.B.)
- Inflammation Research Network, University of Calgary, Calgary, AB T2N 1N4, Canada
- Host-Parasite Interactions, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Andre G. Buret
- Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada; (E.D.); (O.S.); (A.G.B.)
- Inflammation Research Network, University of Calgary, Calgary, AB T2N 1N4, Canada
- Host-Parasite Interactions, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Thibault Allain
- Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada; (E.D.); (O.S.); (A.G.B.)
- Inflammation Research Network, University of Calgary, Calgary, AB T2N 1N4, Canada
- Host-Parasite Interactions, University of Calgary, Calgary, AB T2N 1N4, Canada
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10
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Ikutama R, Peng G, Tsukamoto S, Umehara Y, Trujillo-Paez JV, Yue H, Nguyen HLT, Takahashi M, Kageyama S, Komatsu M, Okumura K, Ogawa H, Ikeda S, Niyonsaba F. Cathelicidin LL-37 Activates Human Keratinocyte Autophagy through the P2X₇, Mechanistic Target of Rapamycin, and MAPK Pathways. J Invest Dermatol 2022; 143:751-761.e7. [PMID: 36455652 DOI: 10.1016/j.jid.2022.10.020] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/30/2022] [Accepted: 10/18/2022] [Indexed: 11/29/2022]
Abstract
Human cathelicidin LL-37 is a multifunctional antimicrobial peptide that exhibits antimicrobial and immunomodulatory activities. LL-37 regulates skin barrier function and was recently reported to activate autophagy in macrophages. Because autophagy deficiency is associated with skin diseases characterized by a dysfunctional epidermal barrier, we hypothesized that LL-37 might regulate the skin barrier through autophagy modulation. We showed that LL-37 activated autophagy in human keratinocytes and three-dimensional skin equivalent models as indicated by increases in LC3 puncta formation, decreases in p62, and autophagosome and autolysosome formation. LL-37‒induced autophagy was suppressed by P2X7 receptor, adenosine monophosphate‒activated protein kinase, and unc-51-like kinase 1 inhibitors, suggesting that the P2X7, adenosine monophosphate‒activated protein kinase, and unc-51-like kinase 1 pathways are involved. Moreover, LL-37 enhanced the phosphorylation of adenosine monophosphate‒activated protein kinase and unc-51-like kinase 1. In addition, LL-37‒mediated autophagy involves the mechanistic target of rapamycin and MAPK pathways. Interestingly, the LL-37‒induced distribution of tight junction proteins and improvement in the tight junction barrier were inhibited in autophagy-deficient keratinocytes and keratinocytes and skin models treated with autophagy inhibitors, indicating that the LL-37‒mediated tight junction barrier is associated with autophagy activation. Collectively, these findings suggest that LL-37 is a potential therapeutic target for skin diseases characterized by dysfunctional autophagy and skin barriers.
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Affiliation(s)
- Risa Ikutama
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ge Peng
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Saya Tsukamoto
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshie Umehara
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | | | - Hainan Yue
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hai Le Thanh Nguyen
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Miho Takahashi
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shun Kageyama
- Department of Physiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Masaaki Komatsu
- Department of Physiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ko Okumura
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hideoki Ogawa
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shigaku Ikeda
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - François Niyonsaba
- Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Faculty of International Liberal Arts, Juntendo University, Tokyo, Japan.
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11
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Jin Z, Sun X, Wang Y, Zhou C, Yang H, Zhou S. Regulation of autophagy fires up the cold tumor microenvironment to improve cancer immunotherapy. Front Immunol 2022; 13:1018903. [PMID: 36300110 PMCID: PMC9589261 DOI: 10.3389/fimmu.2022.1018903] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 09/27/2022] [Indexed: 11/13/2022] Open
Abstract
Immunotherapies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells, have revolutionized the treatment of patients with advanced and metastatic tumors resistant to traditional therapies. However, the immunosuppressed tumor microenvironment (TME) results in a weak response to immunotherapy. Therefore, to realize the full potential of immunotherapy and obstacle barriers, it is essential to explore how to convert cold TME to hot TME. Autophagy is a crucial cellular process that preserves cellular stability in the cellular components of the TME, contributing to the characterization of the immunosuppressive TME. Targeted autophagy ignites immunosuppressive TME by influencing antigen release, antigen presentation, antigen recognition, and immune cell trafficking, thereby enhancing the effectiveness of cancer immunotherapy and overcoming resistance to immunotherapy. In this review, we summarize the characteristics and components of TME, explore the mechanisms and functions of autophagy in the characterization and regulation of TME, and discuss autophagy-based therapies as adjuvant enhancers of immunotherapy to improve the effectiveness of immunotherapy.
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Affiliation(s)
- Zhicheng Jin
- Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Department of Radiation Oncology, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang, China
| | - Xuefeng Sun
- Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Department of Radiation Oncology, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang, China
| | - Yaoyao Wang
- Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College/National Center for Cardiovascular Diseases, Beijing, China
| | - Chao Zhou
- Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Department of Radiation Oncology, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang, China
| | - Haihua Yang
- Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Department of Radiation Oncology, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang, China
- *Correspondence: Suna Zhou, ; HaihuaYang,
| | - Suna Zhou
- Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Department of Radiation Oncology, Taizhou Hospital Affiliated to Wenzhou Medical University, Zhejiang, China
- Department of Radiation Oncology, Xi’an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, China
- *Correspondence: Suna Zhou, ; HaihuaYang,
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12
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Dowdell AS, Cartwright IM, Kitzenberg DA, Kostelecky RE, Mahjoob O, Saeedi BJ, Welch N, Glover LE, Colgan SP. Essential role for epithelial HIF-mediated xenophagy in control of Salmonella infection and dissemination. Cell Rep 2022; 40:111409. [PMID: 36170839 PMCID: PMC9553003 DOI: 10.1016/j.celrep.2022.111409] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 06/21/2022] [Accepted: 09/02/2022] [Indexed: 01/18/2023] Open
Abstract
The intestinal mucosa exists in a state of “physiologic hypoxia,” where oxygen tensions are markedly lower than those in other tissues. Intestinal epithelial cells (IECs) have evolved to maintain homeostasis in this austere environment through oxygen-sensitive transcription factors, including hypoxia-inducible factors (HIFs). Using an unbiased chromatin immunoprecipitation (ChIP) screen for HIF-1 targets, we identify autophagy as a major pathway induced by hypoxia in IECs. One important function of autophagy is to defend against intracellular pathogens, termed “xenophagy.” Analysis reveals that HIF is a central regulator of autophagy and that in vitro infection of IECs with Salmonella Typhimurium results in induction of HIF transcriptional activity that tracks with the clearance of intracellular Salmonella. Work in vivo demonstrates that IEC-specific deletion of HIF compromises xenophagy and exacerbates bacterial dissemination. These results reveal that the interaction between hypoxia, HIF, and xenophagy is an essential innate immune component for the control of intracellular pathogens. Dowdell et al. show that hypoxia, through stabilization of HIF-1α, activates autophagy in intestinal epithelial cells (IECs). Further, the model invasive bacterium Salmonella Typhimurium stabilizes HIF in IECs to trigger anti-bacterial autophagy (xenophagy). This mechanism demonstrates an essential mucosal innate immune response for control of invasive pathogens.
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Affiliation(s)
- Alexander S Dowdell
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA; Rocky Mountain Veterans Hospital, Aurora, CO, USA
| | - Ian M Cartwright
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA; Rocky Mountain Veterans Hospital, Aurora, CO, USA
| | - David A Kitzenberg
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Rachael E Kostelecky
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Omemh Mahjoob
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Bejan J Saeedi
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Nichole Welch
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
| | - Louise E Glover
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA; School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Sean P Colgan
- Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA; Rocky Mountain Veterans Hospital, Aurora, CO, USA.
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13
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Neutrophil-Epithelial Crosstalk During Intestinal Inflammation. Cell Mol Gastroenterol Hepatol 2022; 14:1257-1267. [PMID: 36089244 PMCID: PMC9583449 DOI: 10.1016/j.jcmgh.2022.09.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 09/02/2022] [Accepted: 09/02/2022] [Indexed: 01/31/2023]
Abstract
Neutrophils are the most abundant leukocyte population in the human circulatory system and are rapidly recruited to sites of inflammation. Neutrophils play a multifaceted role in intestinal inflammation, as they contribute to the elimination of invading pathogens. Recently, their role in epithelial restitution has been widely recognized; however, they are also associated with bystander tissue damage. The intestinal epithelium provides a physical barrier to prevent direct contact of luminal contents with subepithelial tissues, which is extremely important for the maintenance of intestinal homeostasis. Numerous studies have demonstrated that transepithelial migration of neutrophils is closely related to disease symptoms and disruption of crypt architecture in inflammatory bowel disease and experimental colitis. There has been growing interest in how neutrophils interact with the epithelium under inflammatory conditions. Most studies focus on the effects of neutrophils on intestinal epithelial cells; however, the effects of intestinal epithelial cells on neutrophils during intestinal inflammation need to be well-established. Based on these data, we have summarized recent articles on the role of neutrophil-epithelial interactions in intestinal inflammation, particularly highlighting the epithelium-derived molecular regulators that mediate neutrophil recruitment, transepithelial migration, and detachment from the epithelium, as well as the functional consequences of their crosstalk. A better understanding of these molecular events may help develop novel therapeutic targets for mitigating the deleterious effects of neutrophils in inflammatory bowel disease.
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14
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Steiner CA, Cartwright IM, Taylor CT, Colgan SP. Hypoxia-inducible factor as a bridge between healthy barrier function, wound healing, and fibrosis. Am J Physiol Cell Physiol 2022; 323:C866-C878. [PMID: 35912990 PMCID: PMC9467472 DOI: 10.1152/ajpcell.00227.2022] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/07/2022] [Accepted: 07/23/2022] [Indexed: 11/22/2022]
Abstract
The healthy mammalian intestine is lined by a single layer of epithelial cells. These cells provide a selectively permeable barrier to luminal contents and normally do so in an efficient and effective manner. Barrier function in the healthy mucosa is provided via several mechanisms including epithelial junctional complexes, mucus production, as well as mucosal-derived antimicrobial proteins. As tissue metabolism is central to the maintenance of homeostasis in the mucosa, intestinal [Formula: see text] levels are uniquely low due to counter-current blood flow and the presence of the microbiota, resulting in the stabilization of the transcription factor hypoxia-inducible factor (HIF). Ongoing studies have revealed that HIF molds normal intestinal metabolism and is central to the coordination of barrier regulation during both homeostasis and active disease. During acute inflammation, HIF is central to controlling the rapid restitution of the epithelium consistent with normal wound healing responses. In contrast, HIF may also contribute to the fibrostenotic response associated with chronic, nonresolving inflammation. As such, HIF may function as a double-edged sword in the overall course of the inflammatory response. Here, we review recent literature on the contribution of HIF to mucosal barrier function, wound healing, and fibrosis.
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Affiliation(s)
- Calen A Steiner
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado
| | - Ian M Cartwright
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
| | - Cormac T Taylor
- School of Medicine, Conway Institute and Systems Biology Ireland, University College Dublin, Dublin, Ireland
| | - Sean P Colgan
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
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15
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Gregory AL, Pensinger DA, Hryckowian AJ. A short chain fatty acid-centric view of Clostridioides difficile pathogenesis. PLoS Pathog 2021; 17:e1009959. [PMID: 34673840 PMCID: PMC8530303 DOI: 10.1371/journal.ppat.1009959] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Clostridioides difficile is an opportunistic diarrheal pathogen responsible for significant morbidity and mortality worldwide. A disrupted (dysbiotic) gut microbiome, commonly engendered by antibiotic treatment, is the primary risk factor for C. difficile infection, highlighting that C. difficile–microbiome interactions are critical for determining the fitness of this pathogen. Here, we review short chain fatty acids (SCFAs): a major class of metabolites present in the gut, their production by the gut microbiome, and their impacts on the biology of the host and of C. difficile. We use these observations to illustrate a conceptual model whereby C. difficile senses and responds to SCFAs as a marker of a healthy gut and tunes its virulence accordingly in order to maintain dysbiosis. Future work to learn the molecular mechanisms and genetic circuitry underlying the relationships between C. difficile and SCFAs will help to identify precision approaches, distinct from antibiotics and fecal transplant, for mitigating disease caused by C. difficile and will inform similar investigations into other gastrointestinal pathogens.
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Affiliation(s)
- Anna L. Gregory
- Department of Medicine, University of Wisconsin School of Medicine & Public Health, Madison, Wisconsin, United States of America
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine & Public Health, Madison, Wisconsin, United States of America
- Microbiology Doctoral Training Program, University of Wisconsin-Madison, Madison, Wisconsin, United States of America
| | - Daniel A. Pensinger
- Department of Medicine, University of Wisconsin School of Medicine & Public Health, Madison, Wisconsin, United States of America
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine & Public Health, Madison, Wisconsin, United States of America
| | - Andrew J. Hryckowian
- Department of Medicine, University of Wisconsin School of Medicine & Public Health, Madison, Wisconsin, United States of America
- Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine & Public Health, Madison, Wisconsin, United States of America
- * E-mail:
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16
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Wei YX, Zheng KY, Wang YG. Gut microbiota-derived metabolites as key mucosal barrier modulators in obesity. World J Gastroenterol 2021; 27:5555-5565. [PMID: 34588751 PMCID: PMC8433617 DOI: 10.3748/wjg.v27.i33.5555] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/24/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
A significant breakthrough in the field of obesity research was the demonstration that an obese phenotype could be manipulated by modulating the gut microbiota. An important next step is to elucidate a human-relevant “map’’ of microbiota-host interactions that regulate the metabolic health of the host. An improved understanding of this crosstalk is a prerequisite for optimizing therapeutic strategies to combat obesity. Intestinal mucosal barrier dysfunction is an important contributor to metabolic diseases and has also been found to be involved in a variety of other chronic inflammatory conditions, including cancer, neurodegeneration, and aging. The mechanistic basis for intestinal barrier dysfunction accompanying metabolic disorders remains poorly understood. Understanding the molecular and cellular modulators of intestinal barrier function will help devise improved strategies to counteract the detrimental systemic consequences of gut barrier breakage. Changes in the composition and function of the gut microbiota, i.e., dysbiosis, are thought to drive obesity-related pathogenesis and may be one of the most important drivers of mucosal barrier dysfunction. Many effects of the microbiota on the host are mediated by microbiota-derived metabolites. In this review, we focus on several relatively well-studied microbial metabolites that can influence intestinal mucosal homeostasis and discuss how they might affect metabolic diseases. The design and use of microbes and their metabolites that are locally active in the gut without systemic side effects are promising novel and safe therapeutic modalities for metabolic diseases.
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Affiliation(s)
- Yan-Xia Wei
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Kui-Yang Zheng
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
| | - Yu-Gang Wang
- Laboratory of Infection and Immunity, Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
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17
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Alexeev EE, Dowdell AS, Henen MA, Lanis JM, Lee JS, Cartwright IM, Schaefer REM, Ornelas A, Onyiah JC, Vögeli B, Colgan SP. Microbial-derived indoles inhibit neutrophil myeloperoxidase to diminish bystander tissue damage. FASEB J 2021; 35:e21552. [PMID: 33826788 DOI: 10.1096/fj.202100027r] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 03/03/2021] [Accepted: 03/08/2021] [Indexed: 01/20/2023]
Abstract
During episodes of acute inflammation, polymorphonuclear leukocytes (PMNs) are actively recruited to sites of inflammation or injury where they provide anti-microbial and wound-healing functions. One enzyme crucial for fulfilling these functions is myeloperoxidase (MPO), which generates hypochlorous acid from Cl- and hydrogen peroxide. The potential exists, however, that uncontrolled the extracellular generation of hypochlorous acid by MPO can cause bystander tissue damage and inhibit the healing response. Previous work suggests that the microbiota-derived tryptophan metabolites 1H-indole and related molecules ("indoles") are protective during intestinal inflammation, although their precise mechanism of action is unclear. In the present work, we serendipitously discovered that indoles are potent and selective inhibitors of MPO. Using both primary human PMNs and recombinant human MPO in a cell-free system, we revealed that indoles inhibit MPO at physiologic concentrations. Particularly, indoles block the chlorinating activity of MPO, a reliable marker for MPO-associated tissue damage, as measured by coulometric-coupled HPLC. Further, we observed direct interaction between indoles and MPO using the established biochemical techniques microscale thermophoresis and STD-NMR. Utilizing a murine colitis model, we demonstrate that indoles inhibit bystander tissue damage, reflected in decreased colon 3-chlorotyrosine and pro-inflammatory chemokine expression in vivo. Taken together, these results identify microbiota-derived indoles that acts as endogenous immunomodulatory compounds through their actions on MPO, suggesting a symbiotic association between the gut microbiota and host innate immune system. Such findings offer exciting new targets for future pharmacological intervention.
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Affiliation(s)
- Erica E Alexeev
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Alexander S Dowdell
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Morkos A Henen
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,Department of Pharmaceutical Organic Chemistry, Mansoura University, Mansoura, Egypt
| | - Jordi M Lanis
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - J Scott Lee
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ian M Cartwright
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Rachel E M Schaefer
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Alfredo Ornelas
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Joseph C Onyiah
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Beat Vögeli
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Sean P Colgan
- Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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18
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Pral LP, Fachi JL, Corrêa RO, Colonna M, Vinolo MAR. Hypoxia and HIF-1 as key regulators of gut microbiota and host interactions. Trends Immunol 2021; 42:604-621. [PMID: 34171295 DOI: 10.1016/j.it.2021.05.004] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/05/2021] [Accepted: 05/07/2021] [Indexed: 12/11/2022]
Abstract
Oxygen (O2) availability is a key factor regulating microbiota composition and the homeostatic function of cells in the intestinal mucosa of vertebrates. Microbiota-derived metabolites increase O2 consumption by intestinal epithelial cells (IECs), reducing its availability in the gut and leading to hypoxia. This physiological hypoxia activates cellular hypoxic sensors that adapt the metabolism and function of IECs and mucosa-resident cells, such as type-3 innate lymphoid cells (ILC3s). In this review, we discuss recent evidence suggesting that the intricate and multidirectional interactions among the microbiota, hypoxia/hypoxic sensors, and mammalian host cells (IECs and ILC3s) determine how the intestinal barrier and host-microbiota-pathogens connections are molded. Understanding these interactions might provide new treatment possibilities for dysbiosis, as well as certain inflammatory and infectious diseases.
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Affiliation(s)
- Laís P Pral
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - José L Fachi
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
| | - Renan O Corrêa
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA.
| | - Marco A R Vinolo
- Laboratory of Immunoinflammation, Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil; Experimental Medicine Research Cluster, Campinas, Brazil; Obesity and Comorbidities Research Center (OCRC), University of Campinas, Campinas, Brazil.
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