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Abstract
The role of resident cells such a synoviocytes and chondrocytes in intra-articular inflammation is well-characterized, however the in vivo gene expression patterns of cells (predominantly leukocytes) in the synovial fluid (SF) of an inflamed joint have never previously been investigated. The aim of this study was to investigate gene expression in SF leukocytes from the inflamed joint cavity after intra-articular lipopolysaccharide (LPS) injection in horses to improve our understanding of the temporal regulation of the intra-articular inflammatory response. Gene expression was investigated in SF samples available from six horses 2, 4, 8 16 and 24 h after experimental induction of inflammation in the radiocarpal joint by lipopolysaccharide (LPS) injection. Leukocytic expression of 43 inflammation-related genes was studied using microfluidic high throughput qPCR (Fluidigm®). Expression of 26 genes changed significantly over the 24 h study period, including pro- and anti-inflammatory genes such as interleukin (IL)1, IL6, tumor necrosis factor (TNF), cyclooxygenase 2 (COX2), IL1 receptor antagonist (IL1RN), IL10, and superoxide dismutase 2 (SOD2), chemokine genes, apoptosis-related genes, and genes related to cartilage turnover (matrix metalloproteinase 8 and tissue inhibitor of metalloproteinase 1). The inflammatory responses appeared to be regulated, as an early increase (at 2 h) in expression of the pro-inflammatory genes IL1, IL6, TNF and COX2 was rapidly followed by increased expression (at 4 h) of several anti-inflammatory genes (IL10, IL1RN and SOD2). Similarly, both pro- and anti-apoptotic gene expression as well as expression of chondrodegenerative and chondroprotective genes were activated in SF leukocytes. Thus, the inflammatory response in leukocytes infiltrating the joint in the acute stage of arthritis was well orchestrated in this single-hit LPS-induced arthritis model. This study is the first to describe gene expression patterns in SF-derived leukocytes in vivo during severe joint inflammation, and the results thus expand our knowledge of basic inflammatory mechanisms in the early local response in an inflamed joint.
Highlights
In arthritis, the responses of the resident cells of the joint, synovio cytes and chondrocytes, are well described
The early phase (2− 4 h after injection) of the lipopolysac charide (LPS)-induced joint inflammation was dominated by proinflammatory responses with increased gene expression of proinflammatory cytokines, cyclooxygenase 2 (COX2), toll-like receptor 4 (TLR4) and chemokines
This was fol lowed by an anti-inflammatory response (4− 8 h after injection), where gene expression of anti-inflammatory cytokines and superoxide dismutase 2 (SOD2) was increased in the leukocytes
Summary
The responses of the resident cells of the joint, synovio cytes and chondrocytes, are well described. Synoviocytes and chondrocytes contribute to the accumulation of pro-inflammatory molecules in synovial fluid (SF), e.g. IL-1β, IL-6 (Ma et al, 2017), and prostaglandin E2 (PGE2) (Campbell et al, 1990) These in turn cause decreased hyaluronan concentration in cartilage (Guerne et al, 1990; Hardy et al, 1998), stimulate bone destruction, loss of proteoglycan, Abbreviations: ECM, Extracellular matrix; MMP, Matrix metalloproteinase; NTC, No template control; PGE2, Prostaglandin E2; OA, Osteoarthritis; RIN, RNA integrity number; ROS, Reactive oxygen species; -RT, Non-reverse transcriptase controls; RT-qPCR, Reverse transcription quantitative polymerase chain reaction; SF, Synovial fluid; WBC, White blood cell count. It was hypothesized that expression pattern of inflammation-related genes would change over the course of intra articular inflammation
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