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

Abstract

Objective 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 post-infectious LA, we analyzed differences in microRNA expression between LA patients with active infection compared with those with post-infectious LA. Methods MicroRNA expression was assayed in synovial fluid (SF) from LA patients before and after oral and IV antibiotic therapy, and from synovial tissue from post-infectious LA patients obtained months after antibiotic therapy. SF and tissue from patients with other forms of arthritis such as rheumatoid arthritis and osteoarthritis were used for comparison groups. Results SF from LA patients during active infection had marked elevation in white blood cells, particularly polymorphonuclear leukocytes, accompanied by elevated miR-223 levels. In contrast, SF from post-antibiotic LA patients contained greater percentages of lymphocytes and mononuclear cells. Post-antibiotic LA SF also exhibited marked inflammatory (miR-146a, miR-155), wound repair (miR-142), and proliferative (miR-17~92) microRNA signatures, and higher levels of these microRNAs correlated with longer arthritis duration. miR-146a, miR-155, miR-142, miR-223, and miR-17~92 were also elevated in synovial tissue in late post-infectious LA, and let-7a was reduced, similar to RA. Conclusions During active infection, microRNA expression in SF reflected an immune response associated with bacterial killing, whereas in post-infectious LA, microRNA 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.

Robust interferon signature and suppressed tissue repair gene expression in synovial tissue from patients with postinfectious,Borrelia burgdorferi‐induced Lyme arthritis

“…The correlations between gene expression profiles in synovium and previous histologic (Londono et al, ) and microRNA (Lochhead et al, ) findings indicated that microRNA expression and expression of other gene signatures were coregulated. For example, the inflammatory/Th1 signatures in postinfectious LA and the inflammatory RA subtype of RA are accompanied by elevated miR‐155 expression.…”

“…MicroRNA (miRNA) expression profiling was also conducted previously using RNA collected from the same patients used in this study (Lochhead et al, ). In the previous study, patients with postinfectious LA and those with other forms of chronic inflammatory arthritis had particularly high expression of pro‐inflammatory miR‐155 and low expression of cell‐cycle regulator microRNA let‐7a in synovial tissue, compared with OA tissue.…”

A joint effort: The interplay between the innate and the adaptive immune system in Lyme arthritis

“…miRNA expression in patients with postinfectious Lyme arthritis was most similar to the expression in RA patients, where miR‐155, miR‐146a, and miR‐223 were prominent in the synovial fluid, synovial tissue, and synovial fibroblasts . Higher levels of miR‐146a, miR‐17, and miR‐233 are also correlated with increased duration of Lyme arthritis . Thus, the miRNA pattern in SF changes during stages of Lyme arthritis, possibly representing the altering nature of Lyme arthritis after bacterial killing.…”

“…Elevated levels of miR‐223 and low levels of miRNAs such as miR‐146a, miR‐155, and miR‐142 were found in synovial fluid of Lyme arthritis patients prior to antibiotic therapy (n = 5). Also, elevated levels of white blood cells, specifically PMNs, were found in SF of these patients . In contrast to postantibiotic persistent Lyme arthritis patients (n = 13), who had higher percentages of lymphocytes and mononuclear cells, and a high expression of miR‐146a, miR‐155, miR‐142, miR‐233, and miR‐17‐92.…”

“…In contrast to postantibiotic persistent Lyme arthritis patients (n = 13), who had higher percentages of lymphocytes and mononuclear cells, and a high expression of miR‐146a, miR‐155, miR‐142, miR‐233, and miR‐17‐92. Let‐7a family levels were reduced . Of note, arthritis in two of these 13 patients resolved after intravenous administration of antibiotics.…”