MicroRNA Expression Shows Inflammatory Dysregulation and Tumor-Like Proliferative Responses in Joints of Patients With Postinfectious Lyme Arthritis.

Abstract

Lyme arthritis (LA) is caused by infection with Borrelia burgdorferi and usually resolves following spirochetal killing with antibiotics. However, in some patients, arthritis persists after antibiotic therapy. To provide insights into underlying pathogenic processes associated with antibiotic-refractory LA (postinfectious LA), we analyzed differences in microRNA (miRNA) expression between LA patients with active infection and those with postinfectious LA. MicroRNA expression was assayed in synovial fluid (SF) from LA patients before and after oral and intravenous antibiotic therapy, and in synovial tissue obtained months after antibiotic therapy from patients with postinfectious LA. SF and tissue from patients with other forms of arthritis, such as rheumatoid arthritis (RA) and osteoarthritis, were used for comparison. SF from LA patients during active infection had marked elevations of white blood cells, particularly polymorphonuclear leukocytes, accompanied by elevated levels of microRNA-223 (miR-223). In contrast, SF from postantibiotic LA patients contained greater percentages of lymphocytes and mononuclear cells. SF from postantibiotic LA patients also exhibited marked inflammatory (miR-146a, miR-155), wound repair (miR-142), and proliferative (miR-17-92) miRNA signatures, and higher levels of these miRNAs correlated with longer arthritis duration. Levels of miR-146a, miR-155, miR-142, miR-223, and miR-17-92 were also elevated in synovial tissue in late postinfectious LA, and levels of let-7a were reduced, similar to RA. During active infection, miRNA expression in SF reflected an immune response associated with bacterial killing, while in postinfectious LA, miRNA expression in SF and synovial tissue reflected chronic inflammation, synovial proliferation, and breakdown of wound repair processes, showing that the nature of the arthritis was altered after spirochetal killing.