Influência do metabolismo na resposta inflamatória da artrite crônica em modelo experimental

Abstract

Rheumatoid arthritis (RA) is the most prevalent rheumatic disease in the world, and its prognosis is related to synovial joints stiffing, associated with pain and swelling. However, RA's effects are not only restricted to joints. Patients with RA have systemic metabolic alterations, leading to an increased risk of developing cardiovascular diseases. When RA is associated with obesity, a disease characterized by the expansion and inflammation of adipose tissue, there is a worse prognosis. However, few studies elucidate the role of metabolism in the severity of rheumatoid arthritis. Thus, this study aimed to evaluate whether the metabolic alterations caused by obesity alter the immune response of chronic experimental arthritis. Male Balb/c mice were fed a high-carb diet (HC) or a chow diet (C) throughout the experimental period. After four weeks, the arthritis induction protocol started with an intra-articular injection of PBS or mBSA (AIA). After the first immunization, we treated animals with 5mg/mL of metformin, administered in the drinking water ad libitum (MET). Therefore, we formed experimental groups (i) C PBS, (ii) C AIA, (iii) HC PBS, (iv) HC AIA, (v) C MET AIA, (vi) HC MET PBS, and (vii) HC MET AIA. On the day of sacrifice, we performed the following procedures: measurement of nociception and total and differential leukocyte count in the knee, visceral adipose tissues, and serum were removed and quantified for glucose measurement. We removed the epididymal adipose tissue and knee for histology. In addition, we used the knee to measure IL-1β and IL-17 cytokines and to assess the myeloperoxidase enzyme (MPO). The animals that received the HC diet did not have a difference in weight but had an increase in the adiposity index, adipocyte area, and blood glucose. This same group had worsening markers of arthritis severity, such as hypernociception, increased neutrophils, IL-1β, and IL-17 cytokines in the joint cavity, and a higher arthritis score. Treatment with metformin in the lean group resulted in a reduction in all metabolic parameters evaluated, such as blood glucose, adipocyte area, and adiposity index, in addition to reduced joint inflammation, evidenced by lower neutrophil counts and reduced MPO enzyme. When evaluating obese animals treated with metformin, it was found that the reduction was in blood glucose and adipocyte area but not in the adiposity index. However, once again, all inflammatory parameters of arthritis were minimized after metformin treatment. Based on this, we found evidence that glucose metabolism influences the inflammatory process in this experimental arthritis model and animals with a diet rich in refined carbohydrates. Our data, therefore, indicate that metformin has therapeutic potential in arthritis associated or not with obesity.