The Role of Macrophages in the Response to TNF Inhibition in Experimental Arthritis

• Published in: The Journal of immunology (1950) Vol. 200; no. 1; pp. 130 - 138
• Main Authors: Huang, Qi-Quan, Birkett, Robert, Doyle, Renee, Shi, Bo, Roberts, Elyssa L, Mao, Qinwen, Pope, Richard M
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 01.01.2018
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Antirheumatic Agents - therapeutic use; Apoptosis; Arthritis; Arthritis, Experimental - drug therapy; Arthritis, Rheumatoid - drug therapy; CCR7 protein; Cell Line; Chemokine CCL19 - metabolism; Chemokine CCL21 - metabolism; Chemotaxis - genetics; Enzyme-linked immunosorbent assay; Flow cytometry; Histology; Humans; Immunohistochemistry; Infliximab; Infliximab - therapeutic use; Inhibition; Lymph nodes; Lymphatic system; Macrophages; Macrophages - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Monoclonal antibodies; Monocyte chemoattractant protein 1; Monocytes; Polymerase chain reaction; Receptors, CCR7 - genetics; Receptors, CCR7 - metabolism; Rheumatoid arthritis; Rodents; Synovial fluid; Transgenic mice; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1700229

The reduction of synovial tissue macrophages is a reliable biomarker for clinical improvement in patients with rheumatoid arthritis (RA), and macrophages are reduced in synovial tissue shortly after initiation of TNF inhibitors. The mechanism for this initial response is unclear. These studies were performed to identify the mechanisms responsible for the initial reduction of macrophages following TNF inhibition, positing that efflux to draining lymph nodes was involved. RA synovial tissue and synovial fluid macrophages expressed CCR7, which was increased in control macrophages following incubation with TNF-α. Human TNF transgenic (hTNF-Tg) mice were treated with infliximab after development of arthritis. Ankles were harvested and examined by histology, immunohistochemistry, quantitative RT-PCR, ELISA, and flow cytometry. hTNF-Tg mice treated with infliximab demonstrated significant clinical and histologic improvement 3 d after the initiation of therapy, at which time Ly6C macrophages were significantly reduced in the ankles. However, no evidence was identified to support a role of macrophage efflux to draining lymph nodes following treatment with infliximab. In contrast, apoptosis of Ly6C macrophages in the ankles and popliteal lymph nodes, decreased migration of monocytes into the ankles, and a reduction of CCL2 were identified following the initiation of infliximab. These observations demonstrate that Ly6C macrophage apoptosis and decreased ingress of circulating monocytes into the joint are responsible for the initial reduction of macrophages following infliximab treatment in hTNF-Tg mice.