Impaired lymphatic contraction associated with immunosuppression

Abstract

To trigger an effective immune response, antigen and antigen-presenting cells travel to the lymph nodes via collecting lymphatic vessels. However, our understanding of the regulation of collecting lymphatic vessel function and lymph transport is limited. To dissect the molecular control of lymphatic function, we developed a unique mouse model that allows intravital imaging of autonomous lymphatic vessel contraction. Using this method, we demonstrated that endothelial nitric oxide synthase (eNOS) in lymphatic endothelial cells is required for robust lymphatic contractions under physiological conditions. By contrast, under inflammatory conditions, inducible NOS (iNOS)-expressing CD11b + Gr-1 + cells attenuate lymphatic contraction. This inhibition of lymphatic contraction was associated with a reduction in the response to antigen in a model of immune-induced multiple sclerosis. These results suggest the suppression of lymphatic function by the CD11b + Gr-1 + cells as a potential mechanism of self-protection from autoreactive responses during on-going inflammation. The central role for nitric oxide also suggests that other diseases such as cancer and infection may also mediate lymphatic contraction and thus immune response. Our unique method allows the study of lymphatic function and its molecular regulation during inflammation, lymphedema, and lymphatic metastasis.

Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

“…Using the K14-VEGFR-3-Ig mice model, we previously showed how impaired lymph drainage and the absence of dermal LECs resulted in impaired acquired tolerance to contact hypersensitivity, although these mice could mount a systemic T cell response (60). In the experimental autoimmune encephalomyelitis model, impaired lymphatic contraction and fluid drainage were reported to result in an autoimmune response (61). Together, this suggests that impaired lymphatic drainage translates to an inappropriately activated immune response.…”

Lymphatic vessels and tertiary lymphoid organs

“…The use of inflammation-induced LVs might be beneficial in these situations. However, as noted above, the lymphangiogenesis that initially occurs in acute inflammation can result in defective LVs (44); therefore, it is crucial to understand the factors that generate and maintain functional, mature, LVs.…”

Sensitivity analysis of near-infrared functional lymphatic imaging

“…The ability to measure this response non-invasively would be particularly useful given recent findings that certain immune cells migrate to the lymphatics and release NO as a means of regulating local lymphatic draining. 29 The gold standard for quantifying lymphatic pump function has been to utilize diameter tracking of contracting vessels to calculate parameters such as stroke volume and ejection fraction. These temporal traces of diameter changes have been achieved in isolated vessel preparations, 31,44 invasive in vivo intravital brightfield microscopy, 33,45 and more recently through invasive intravital fluorescence microscopy using vessels filled with FITC labeled dextran.…”

“…Furthermore, the current state of the art for studying lymphatic contractile dynamics and their biophysical and molecular regulation in vivo requires invasive, terminal procedures, [27][28][29][30] but NIR lymphatic imaging may have the potential to generate similar data regarding lymphatic function in a completely noninvasive manner. Therefore, we will validate the performance of the NIR imaging system to detect functional changes in lymphatic transport by intentionally modulating lymphatic contractility in vivo using nitric oxide (NO) and performing in vivo NIR imaging to detect the resulting changes in lymphatic function.…”