Lymphatics regulation of the inflammatory clotting creates the natural on-off switch for the immune ignorance that allows subcutaneous allografting

Abstract

The ability of lymph to clot indicates that similar to blood vessels lymphatics must have means to counteract this process. We analyzed their hemostatic properties, tailoring them for the potential therapeutic applications. Inflammatory stimuli induced tissue factor-dependent focal lymph clotting while blocking thrombomodulin lead to widespread but also transient occlusion of collecting vessels. Decellularization of lymphatics resulted in tissue factor-independent lymphatic occlusion by wide-spread and persistent lymph clots. These decellularized basement membrane remnants of collectors were capable of macromolecules drainage and leukocytes transit only when lymph clotting was inhibited with heparin. In occluded ghost vessels, fibrin was replaced with transient basement membrane-rich inclusions to be eventually reperfused. During regeneration, ghost vessels were filled with granuloma-like clusters of antigen-presenting and T cells. Despite that, immune response against allografts placed under non-drained skin was not developed as long lymphatics remained occluded, and graft survival was prolonged together with the delay of lymphatic regeneration with anti-lymphangiogenic therapy. Other potential applications of lymphatic hemostatic control functions include blocking pathogen or metastasis spread but also should be considered in the treatment of lymphedema.

Homeostatic maintenance of the lymphatic vasculature

“…Lymphatic vessels and LNs also contribute to innate immunity by limiting pathogen spread through neutralization by LN-resident subcapsular sinus macrophages and recruited neutrophils [3]. Lymphatic vessels may also directly limit pathogen spread through inflammatory stimuli-induced and tissue factor-dependent focal lymph clotting that transiently occludes collecting vessels [4], and by providing an 'innate-like' barrier to viral dissemination through type I interferon (IFN)-mediated remodeling of lymphatic capillaries to shut down fluid transport [5]. Lymphatic vessels have additional specialized functions in different organs (Figure 1) [1,2,6].…”