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

Authors
  • Huang, Qi-Quan1
  • Birkett, Robert1
  • Doyle, Renee1
  • Shi, Bo1
  • Roberts, Elyssa L1
  • Mao, Qinwen2
  • Pope, Richard M3
  • 1 Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and.
  • 2 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
  • 3 Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; and [email protected]
Type
Published Article
Journal
The Journal of Immunology
Publisher
The American Association of Immunologists
Publication Date
Jan 01, 2018
Volume
200
Issue
1
Pages
130–138
Identifiers
DOI: 10.4049/jimmunol.1700229
PMID: 29150565
Source
Medline
License
Unknown

Abstract

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.

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