| First Author | Qadri M | Year | 2018 |
| Journal | J Immunol | Volume | 200 |
| Issue | 2 | Pages | 758-767 |
| PubMed ID | 29196459 | Mgi Jnum | J:257356 |
| Mgi Id | MGI:6110538 | Doi | 10.4049/jimmunol.1700713 |
| Citation | Qadri M, et al. (2018) Role of CD44 in Regulating TLR2 Activation of Human Macrophages and Downstream Expression of Proinflammatory Cytokines. J Immunol 200(2):758-767 |
| abstractText | 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-kappaB nuclear translocation, IL-1 beta and TNF-alpha gene expression, and protein concentrations were determined. Anti-CD44 Ab and HA treatments reduced NF-kappaB translocation, IL-1beta and TNF-alpha 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-kappaB translocation by HA. CD44 knockdown reduced NF-kappaB nuclear translocation and downstream IL-1beta and TNF-alpha protein production following TLR2 receptor stimulation (p < 0.001). CD44(+/+) murine bone marrow-derived macrophages produced higher TNF-alpha compared with CD44(-/-) macrophages following TLR2 stimulation (p < 0.01). HA dose-dependently inhibited TLR2-induced TNF-alpha production by murine bone marrow-derived macrophages (p < 0.001). OA synovial fluids (SF) stimulated TLR2 and TLR4 receptors and induced NF-kappaB 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-kappaB 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. |
