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

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.

CSF-1 in Inflammatory and Arthritic Pain Development

“…We have recently found that there is a requirement for GM-CSF in the same exogenous TNFdriven model (40), again indicating a link between the activities of the two CSFs in question. It has been proposed that the successful treatment of the TNF transgenic mouse arthritis model with a TNF inhibitor was due to decreased migration of monocytes and/or increased synovial macrophage apoptosis (64); based on our finding, perhaps CSF-1 could be involved in regulating these functions. Also, and encouragingly for any clinical applications arising from our above findings, the benefit of early but not late CSF-1 blockade parallels that of anti-TNF blockade for ZIA (Fig.…”

Polarization of Rheumatoid Macrophages by TNF Targeting Through an IL-10/STAT3 Mechanism

“…Infiltrating synovial macrophages originate from blood monocytes. These macrophages are considered as short lifespan cells constantly recruited in the inflammatory synovium: they experience activation-induced cell death (34, 35), apoptosis induced by therapeutic agents (22, 32, 36), and eventually efflux from synovium (37). We used monocyte-derived macrophages submitted to pro-inflammatory conditioning to model the contribution of these infiltrating macrophages to rheumatoid synovitis.…”

Effects of myeloid cell-restricted TNF inhibitors in vitro and in vivo

“…Most likely, both of these macrophage subpopulations also express of F4/80 and CD11b and, thus, can be targeted by MYSTIs in order to retain and inhibit TNF on their cell surface. It was shown that neutralization of TNF may affect the phenotype of monocytes and macrophages both at the systemic level and locally in the inflamed joint . Identification of individual cellular molecular markers could contribute to the development of new therapeutic approaches for targeting pathogenic cells involved in inflammation, while maintaining the functional activity of anti‐inflammatory macrophages in RA.…”