Adenosine deaminase modulates metabolic remodeling and orchestrates joint destruction in rheumatoid arthritis
| Autor: | Venketesh Sivaramakrishnan, Rahul Ray, Saibharath Simha Reddy Santha, Sai Krishna Srimadh Bhagavatham, Polani B. Seshagiri, Vishnu Kannan, Sujith Kumar Pulukool, Narsimulu Gumdal, Divya Sridharan, Sai Mangala Divi, Ashish Pargaonkar, Damodaram Potikuri, Ashwin Ashok Naik, Prakash Khanchandani, K. Narasimhan, Rajesh Babu Dandamudi |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Adenosine Deaminase medicine.medical_treatment Osteoclasts Diseases Biochemistry Arthritis Rheumatoid 0302 clinical medicine Adenosine deaminase Rheumatic diseases immune system diseases Synovial Fluid Synoviocyte proliferation Multidisciplinary biology hemic and immune systems Middle Aged Cytokine Rheumatoid arthritis Cytokines Medicine Tumor necrosis factor alpha Female medicine.symptom medicine.drug Cell biology congenital hereditary and neonatal diseases and abnormalities Science Inflammation Article Autoimmune Diseases 03 medical and health sciences medicine Humans 030203 arthritis & rheumatology business.industry Macrophages Mesenchymal stem cell nutritional and metabolic diseases medicine.disease Adenosine Computational biology and bioinformatics enzymes and coenzymes (carbohydrates) 030104 developmental biology Immunology biology.protein Leukocytes Mononuclear business Biomarkers |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-22 (2021) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Rheumatoid Arthritis (RA) is a chronic autoimmune disease associated with inflammation and joint remodeling. Adenosine deaminase (ADA), a risk factor in RA, degrades adenosine, an anti-inflammatory molecule, resulting in an inflammatory bias. We present an integrative analysis of clinical data, cytokines, serum metabolomics in RA patients and mechanistic studies on ADA-mediated effects on in vitro cell culture models. ADA activity differentiated patients into low and high ADA sets. The levels of the cytokines TNFα, IFNγ, IL-10, TGFβ and sRANKL were elevated in RA and more pronounced in high ADA sets. Serum metabolomic analysis shows altered metabolic pathways in RA which were distinct between low and high ADA sets. Comparative analysis with previous studies shows similar pathways are modulated by DMARDs and biologics. Random forest analysis distinguished RA from control by methyl-histidine and hydroxyisocaproic acid, while hexose-phosphate and fructose-6-phosphate distinguished high ADA from low ADA. The deregulated metabolic pathways of High ADA datasets significantly overlapped with high ADA expressing PBMCs GEO transcriptomics dataset. ADA induced the death of chondrocytes, synoviocyte proliferation, both inflammation in macrophages and their differentiation into osteoclasts and impaired differentiation of mesenchymal stem cells to osteoblasts and mineralization. PBMCs expressing elevated ADA had increased expression of cytokines and P2 receptors compared to synovial macrophages which has low expression of ADA. Our data demonstrates increased cytokine levels and distinct metabolic signatures of RA based on the ADA activity, suggests an important role for ADA in the pathophysiology of RA joints and as a potential marker and therapeutic target in RA patients. |
| Databáze: | OpenAIRE |
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