Abstract
IntroductionA pivotal effect of lymphatic vessel (LV) function in joint homeostasis was identified in the tumor necrosis factor-transgenic (TNF-Tg) mouse model of rheumatoid arthritis (RA). Specifically, loss of LV contractions is associated with progressive synovitis and erosions. Furthermore, draining lymph node expansion is a biomarker of arthritic progression, and both macrophages and lymphatic endothelial cells express inducible nitric oxide synthase (iNOS), which disrupts LV contraction and transport of immune cells to the draining lymph nodes. Therefore, to directly assess these relationships, we tested the hypothesis that TNF-Tg mice with global genetic ablation of iNOS (iNOS−/−) will show delayed draining lymph node expansion, maintained LV contractions, and decreased synovitis and erosions.MethodiNOS−/−× TNF-Tg female and male mice, and control littermates (iNOS−/−, TNF-Tg, and WT), were examined with (1) ultrasound to determine popliteal lymph node (PLN) volume and (2) near-infrared imaging (NIR) to assess popliteal LV contraction frequency, and differences between genotypes were assessed at 3, 4, 5, and 6 months of age. Knees and PLN were harvested at 4 months in females and 6 months in males, to assess synovitis, bone erosions, and cellular accumulation in PLN sinuses via histology.ResultsInitially, an increase in PLN volume was observed for both female and male iNOS−/−× TNF-Tg and TNF-Tg compared to their WT and iNOS−/− counterparts at 2 and 3 months, respectively. Subsequently, TNF-Tg PLNs continue to increase in volume, while iNOS−/−× TNF-Tg did not increase in volume from the initial timepoints. WT and iNOS−/− PLN volume was unchanged throughout the experiment. LV contraction frequency was increased at 4 months in females and 5 months in males, in the iNOS−/−× TNF-Tg mice compared to the TNF-Tg. Synovitis and erosions were moderately reduced in iNOS−/−× TNF-Tg versus TNF-Tg knees in females, while no differences in knee pathology were observed in males.ConclusionsGenetic iNOS ablation maintains draining lymph node volume and LV function during TNF-induced inflammatory arthritis and is associated with moderately decreased joint inflammation and damage.
Highlights
A pivotal effect of lymphatic vessel (LV) function in joint homeostasis was identified in the tumor necrosis factor-transgenic (TNF-Tg) mouse model of rheumatoid arthritis (RA)
Evidence for a role of inducible nitric oxide synthase (iNOS) in LV loss of function in arthritis comes from studies demonstrating inflammationinduced iNOS in lymphatic endothelial cells (LECs) and recovery of LV contractions following chemical inhibition of iNOS [16, 17]. iNOS inhibition improves lymphatic function in obese mice, a chronic inflammatory setting [18]. These findings indicate that chronic inflammation induces structural and functional changes to LVs, including the overproduction of iNOS, which inhibits LV contractility and lymphatic drainage from inflamed joints
To assess the contribution of iNOS to this phenotype, we measured whole body weights over time and found that both female TNF-Tg and iNOS−/−× TNF-Tg mice had significantly similar decreased weight at 3 and 4 months of age compared to Wild type (WT) and iNOS−/− (Fig. 1a)
Summary
A pivotal effect of lymphatic vessel (LV) function in joint homeostasis was identified in the tumor necrosis factor-transgenic (TNF-Tg) mouse model of rheumatoid arthritis (RA). The lymphangion, the functional unit of the lymphatic collecting vessels, generates tone and intrinsic pulsatile contractions that propel fluid from which progresses towards draining lymph nodes (LNs). These contractions are generated by a tightly controlled cascade of signaling molecules to generate the required tone and subsequent contractions followed by relaxation of the vessel [3]. The balance between Ca2+ flux which shortens myosin filaments and nitric oxide (NO) release which lengthens the filaments regulates lymph fluid movement via a series of contractions Pathologic disruptions of these contractile events may contribute to buildup of fluid during chronic inflammation
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