Macrophage Activation in the Synovium of Healthy and Osteoarthritic Equine Joints

Abstract

Synovitis is a major component of osteoarthritis and is driven primarily by macrophages. Synovial macrophages are crucial for joint homeostasis (M2-like phenotype), but induce inflammation (M1-like) when regulatory functions become overwhelmed. Macrophage phenotypes in synovium from osteoarthritic and healthy joints are poorly characterized; however, comparative knowledge of their phenotypes during health and disease is paramount for developing targeted treatments. This study compared patterns of macrophage activation in healthy and osteoarthritic equine synovium and correlated histology with cytokine/chemokine profiles in synovial fluid. Synovial histology and immunohistochemistry for M1-like (CD86), M2-like (CD206, IL-10), and pan macrophage (CD14) markers were performed on biopsies from 29 healthy and 26 osteoarthritic equine joints. Synovial fluid cytokines (MCP-1, IL-10, PGE2, IL-1β, IL-6, TNF-α, IL-1ra) and growth factors (GM-CSF, SDF-1α+β, IGF-1, and FGF-2) were quantified. Macrophage phenotypes were not as clearly defined in vivo as they are in vitro. All macrophage markers were expressed with minimal differences between OA and normal joints. Expression for all markers increased proportionate to synovial inflammation, especially CD86. Synovial fluid MCP-1 was higher in osteoarthritic joints while SDF-1 and IL-10 were lower, and PGE2 concentrations did not differ between groups. Increased CD14/CD86/CD206/IL-10 expression was associated with synovial hyperplasia, consistent with macrophage recruitment and activation in response to injury. Lower synovial fluid IL-10 could suggest that homeostatic mechanisms from synovial macrophages became overwhelmed preventing inflammation resolution, resulting in chronic inflammation and OA. Further investigations into mechanisms of arthritis resolution are warranted. Developing pro-resolving therapies may provide superior results in the treatment of OA.

Bone marrow mononuclear cells for joint therapy: The role of macrophages in inflammation resolution and tissue repair

“…Nonetheless, in situations of extensive or continuing tissue damage, the sustained inflammatory response decreases the capacity of macrophages to produce anti-inflammatory, or more correctly, pro-resolving molecules ( e.g. , IL-10 and IGF-1), impairing mechanisms of inflammation resolution and leading to chronic inflammation[ 45 , 47 ]. Ultimately, the perpetually increased production of cytokines and activation of catabolic enzymes causes further damage or aberrant remodeling of joint tissues[ 5 , 20 , 48 ].…”

“…To better understand the roles of macrophages in vivo, we recently assessed the patterns of macrophage phenotype activation in the synovium from healthy equine joints ( n = 29) and compared to that of joints with naturally occurring OA ( n = 26)[ 47 ]. We evaluated the synovial expression of widely used M1-, M2-like and pan macrophages markers [cluster of differentiation (CD)14 (pan-marker), CD86 (M1-like), CD206, and IL-10 (M2-like)] and correlated these findings with synovial histology.…”

“…However, in OA joints these markers increased proportionate to synovial inflammation , especially CD86. These findings were associated with hyperplasia of the synovial lining, which reflects increased macrophage recruitment and activation in response to injury[ 47 , 62 ].…”

“…Among 12 cytokines assayed in that study[ 47 ], concentrations of stromal cell-derived factor (SDF)-1 and IL-10 were lower in synovial fluid from osteoarthritic joints, while macrophage chemoattractant protein (MCP)-1 was higher. Upon inflammatory stimuli, synovial fibroblasts release high concentrations of MCP-1.…”

“…Elevated MCP-1 in synovial fluid from osteoarthritic joints, combined with hyperplasia of the synovial intima characterizes a fibroblast-mediated recruitment of macrophages to the synovium in response to injury[ 63 ]. On the other hand, SDF-1 is an essential chemokine in the recruitment of macrophages during inflammation resolution[ 47 , 64 - 66 ]. Macrophages are the main source of IL-10[ 7 , 67 ], an essential cytokine for cartilage homeostasis and tissue repair[ 8 , 9 , 68 , 69 ].…”