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JOURNAL ARTICLE
RESEARCH SUPPORT, N.I.H., EXTRAMURAL
Role of CD44 in Regulating TLR2 Activation of Human Macrophages and Downstream Expression of Proinflammatory Cytokines.
Journal of Immunology 2018 January 16
Osteoarthritis (OA) is a low-grade chronic inflammatory joint disease. Innate immunity contributes to OA progression, mediated by TLR2 and TLR4. We evaluated the role of cluster determinant 44 (CD44), a transmembrane glycoprotein, in regulating TLR2-linked macrophage activation and resultant proinflammatory responses. TLR2 stimulation was performed on differentiated THP-1 macrophages in the presence or absence of a CD44-specific Ab or hyaluronan (HA). NF-κB nuclear translocation, IL-1 β and TNF-α gene expression, and protein concentrations were determined. Anti-CD44 Ab and HA treatments reduced NF-κB translocation, IL-1β and TNF-α expression, and production ( p < 0.001). Inhibition of proinflammatory response in macrophages by HA was mediated by CD44. Protein phosphatase 2A mediated the reduction in NF-κB translocation by HA. CD44 knockdown reduced NF-κB nuclear translocation and downstream IL-1β and TNF-α protein production following TLR2 receptor stimulation ( p < 0.001). CD44+/+ murine bone marrow-derived macrophages produced higher TNF-α compared with CD44-/- macrophages following TLR2 stimulation ( p < 0.01). HA dose-dependently inhibited TLR2-induced TNF-α production by murine bone marrow-derived macrophages ( p < 0.001). OA synovial fluids (SF) stimulated TLR2 and TLR4 receptors and induced NF-κB translocation in THP-1 macrophages. Anti-CD44 Ab treatment significantly reduced macrophage activation by OA SF ( p < 0.01). CD44 regulated TLR2 responses in human macrophages, whereby a reduction in CD44 levels or engagement of CD44 by its ligand (HA) or a CD44-specific Ab reduced NF-κB translocation and downstream proinflammatory cytokine production. A CD44-specific Ab reduced macrophage activation by OA SF, and CD44 is a potentially novel target in OA treatment.
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