Reciprocal regulation of pro-inflammatory Annexin A2 and anti-inflammatory Annexin A1 in the pathogenesis of rheumatoid arthritis
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Annexin A2 has been implicated in several immune modulated diseases including Rheumatoid arthritis (RA) pannus formation. The most relied treatment option for RA pathogenesis is glucocorticoids. Glucocorticoids regulate the synthesis, phosphorylation and cellular deposition of Annexin A1. This annexin mediates the anti-inflammatory actions of glucocorticoids. These two first characterized members of annexin superfamily proteins acts reciprocally, one as an anti-inflammatory and the other proinflammatory in nature. The possibility of these molecules as soluble biomarkers and as an upstream regulator of major cytokine devastation at RA microenvironment has not been previously explored. Current study elucidates the reciprocal regulation of these two annexins in RA pathogenesis. These Annexin A2/A1 and downstream cytokines in RA serum were analysed by ELISA. Western blot, Immunocytochemistry, immunoprecipitation and Immunohistochemistry were adapted to analyse these molecules in tissue and synovial fibroblasts and also in different experimental conditions. Significant increase in the level of Annexin A2 was noticed in naïve RA patients compared to controls (14.582 ± 1.766 ng/ml vs. 7.37 ± 1.450 ng/ml; p ≤ 0.001). In remission cases significant low levels was detected. On the contrary, significant decrease in the level of Annexin A1 was noticed in naïve RA patients compared to healthy controls (12.322 ± 2.91 vs. 16.998 ± 4.298 ng/ml; p ≤ 0.001), wherein remission cases serum Annexin A1 was significantly high. The knockdown of proinflammatory Annexin A2 by siRNA/antibody treatment could mimic the glucocorticoid treatment as which induced cellular Annexin A1 and membrane translocation resulting in the terminal action. Current data elucidating the regulatory interplay between Annexin A2 and Annexin A1 in RA pathogenesis.
KeywordsRheumatoid arthritis Proinflammatory mediators Annexin A2 Annexin A1 Inflammatory cytokines
Authors would like to acknowledge the technical help rendered by Leonard Clinton D’souza and Dr. Vishwas Kaveeshwara.
Conceived the idea and designed the experiments: VH and PKS. Helped in clinical sample collection and correlated the clinical relevance to the study: VH, JKV and USD. Performed the experiments: SE, AB and PKS. Analysed the data (pathology): USD. Analysed the data (statistical analysis): PKS and AB. Wrote the paper: VH, JKV and PKS. Supervised the overall study: PKS.
This work was supported by funding from Arthritis Super speciality center Hubli, Karnataka. India.
Compliance with ethical standards
Conflict of interest
The authors have declared that no competing interests exist.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The current study protocol was approved by SDM College of Medical Sciences and Hospital, Institutional Ethical Board (Approval No. 0507, 2015–2016).
Even though spare samples were used for the study, informed consent was obtained from all individual participants included in the study.
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