Abstract
PurposeInflammation is involved in many disease processes. However, accurate imaging tools permitting diagnosis and characterization of inflammation are still missing. As inflamed tissues exhibit a high rate of glycolysis, pyruvate metabolism may offer a unique approach to follow the inflammatory response and disease progression. Therefore, the aim of the study was to follow metabolic changes and recruitment of inflammatory cells after onset of inflammation in arthritic ankles using hyperpolarized 1-13C-pyruvate magnetic resonance spectroscopy (MRS) and 19F magnetic resonance imaging (MRI), respectively.ProcedureExperimental rheumatoid arthritis (RA) was induced by intraperitoneal injection of glucose-6-phosphate-isomerase-specific antibodies (GPI) containing serum. To monitor pyruvate metabolism, the transformation of hyperpolarized 1-13C-pyruvate into hyperpolarized 1-13C-lactate was followed using MRS. To track phagocytic immune cell homing, we intravenously injected a perfluorocarbon emulsion 48 h before imaging. The animals were scanned at days 1, 3, or 6 after GPI-serum injection to examine the different stages of arthritic inflammation. Finally, to confirm the pyruvate metabolic activity and the link to inflammatory cell recruitment, we conducted hematoxylin-eosin histopathology and monocarboxylase transporter (MCT-1) immune histochemistry (IHC) of inflamed ankles.ResultsHyperpolarized 1-13C-pyruvate MRS revealed a high rate of lactate production immediately at day 1 after GPI-serum transfer, which remained elevated during the progression of the disease, while 19F-MRI exhibited a gradual recruitment of phagocytic immune cells in arthritic ankles, which correlated well with the course of ankle swelling. Histopathology and IHC revealed that MCT-1 was expressed in regions with inflammatory cell recruitment, confirming the metabolic shift identified in arthritic ankles.ConclusionsOur study demonstrated the presence of a very early metabolic shift in arthritic joints independent of phagocytic immune cell recruitment. Thus, hyperpolarized 1-13C-pyruvate represents a promising tracer to monitor acute arthritic joint inflammation, even with minor ankle swelling. Furthermore, translated to the clinics, these methods add a detailed characterization of disease status and could substantially support patient stratification and therapy monitoring.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease affecting 1– 2 % of the worldwide population and causes severe disabilities
Hyperpolarized 1-13C-pyruvate magnetic resonance spectroscopy (MRS) revealed a high rate of lactate production immediately at day 1 after glucose-6-phosphate-isomerase-specific antibodies (GPI)-serum transfer, which remained elevated during the progression of the disease, while 19F-magnetic resonance imaging (MRI) exhibited a gradual recruitment of phagocytic immune cells in arthritic ankles, which correlated well with the course of ankle swelling
Histopathology and immune histochemistry (IHC) revealed that MCT-1 was expressed in regions with inflammatory cell recruitment, confirming the metabolic shift identified in arthritic ankles
Summary
Rheumatoid arthritis (RA) is an autoimmune disease affecting 1– 2 % of the worldwide population and causes severe disabilities. The disease is characterized by a dense inflammatory cell infiltrate in the joints, proliferation of synovial cells, angiogenesis, and pannus formation. This chronic inflammation of the synovial tissues leads to cartilage and bone destruction, and to joint deformity and infirmity [1]. The current diagnostic tools in patients rely on clinical examination, blood tests, radiography, power Doppler ultrasonography, computed tomography, or magnetic resonance imaging (MRI), but lack specificity and are only capable of identifying rather advanced stages of arthritic joint diseases [2]. There is a critical need for robust diagnostic methods that are able to identify early inflammatory processes within the inflamed joints, even before severe joint and cartilage destruction
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