Brief Report: Treatment of Tumor Necrosis Factor–Transgenic Mice With Anti–Tumor Necrosis Factor Restores Lymphatic Contractions, Repairs Lymphatic Vessels, and May Increase Monocyte/Macrophage Egress

Abstract

Background Recent studies have demonstrated that there is an inverse relationship between lymphatic egress and inflammatory arthritis in affected joints. As a model, TNF-transgenic (TNF-Tg) mice develop advanced arthritis following draining lymph node collapse, and loss of lymphatic contractions downstream of inflamed joints. As it is unknown if these lymphatic deficits are reversible, we tested the hypothesis that anti-TNF therapy reduces advanced inflammatory-erosive arthritis, associated with restoration of lymphatic contractions, repair of damaged lymphatic vessels, and evidence of increased monocyte egress. Methods TNF-Tg mice with advanced arthritis and collapsed popliteal lymph nodes (PLN) were treated with anti-TNF monoclonal antibody (10 mg/kg weekly) or placebo for 6-weeks, and effects on knee synovitis, efferent lymphatic vessel ultrastructure and function, and PLN cellularity were assessed by ultrasound, histology, transmission electron microscopy (TEM), near infrared indocyanine green (NIR-ICG) imaging, and flow cytometry, respectively. Results Anti-TNF therapy significantly decreased synovitis ~5-fold (p<0.05 vs. placebo), restored lymphatic contractions, and significantly increased PLN monocytes/macrophages ~2-fold (p<0.05 vs. placebo). TEM demonstrated large activated macrophages attached to damaged lymphatic endothelium in mice with early arthritis, extensively damaged lymphatic vessels in placebo-treated mice with advanced arthritis, and rolling leukocytes in repaired lymphatic vessels in mice responsive to anti-TNF therapy. Conclusion These findings support the concept that anti-TNF therapy ameliorates inflammatory-erosive arthritis, in part, via restoration of lymphatic vessel contractions and potential enhancement of inflammatory cell egress.

Cardiac lymphatics in health and disease

“…Experimental studies have revealed that immune cell-derived pro-inflammatory mediators released during an acute immune reaction, including TNFα, IL1β, and IFNγ but also nitric oxide (NO . ) produced at high levels by inducible nitric oxidase synthase (iNOS)-expressing cells, leads to lymphatic transport dysfunction 156 . Indeed, in vivo imaging studies have shown that inflammatory cytokines induce button to zipper transformation of LEC junctions and acute inflammation is often associated with reduced precollector/collector pumping with a reduction of the frequency and/or amplitude in lymphangion contractions.…”

Attenuated Joint Tissue Damage Associated With Improved Synovial Lymphatic Function Following Treatment With Bortezomib in a Mouse Model of Experimental Posttraumatic Osteoarthritis

“…Inducible NOS directly affects lymphatic muscle cells via excess nitric oxide . We observed that in mice carrying the tumor necrosis factor transgene (TNF‐Tg), a model of rheumatoid arthritis (RA), macrophages were attached to LECs in the collecting lymphatic vessel that drains the inflamed joints . However, whether macrophages affect LEC function directly remains to be determined.…”

Lymphatic delivery of etanercept via nanotopography improves response to collagen-induced arthritis

“…When used in combination with adjuvant-induced arthritis, and genetic models (such as TNF-Tg mice), the CIA rat model provides an efficient means for predicting therapeutic efficacy in humans [38]. Since completing our work, another study in TNF-Tg animals has shown that systemic IP administration of anti-TNF drugs increase the lymphatic pump [14], in agreement with our data on early CIA progression in rats treated with etanercept versus untreated CIA rats. Extension of this work to adjuvant-induced arthritis, genetic models of RA, and human RA patients remains to be shown.…”