Regulation of Immune Function by the Lymphatic System in Lymphedema

Abstract

The lymphatic vasculature has traditionally been thought to play a passive role in the regulation of immune responses by transporting antigen presenting cells and soluble antigens to regional lymph nodes. However, more recent studies have shown that lymphatic endothelial cells regulate immune responses more directly by modulating entry of immune cells into lymphatic capillaries, presenting antigens on major histocompatibility complex proteins, and modulating antigen presenting cells. Secondary lymphedema is a disease that develops when the lymphatic system is injured during surgical treatment of cancers or is damaged by infections. We have used mouse models of lymphedema in order to understand the effects of chronic lymphatic injury on immune responses and have shown that lymphedema results in a mixed T helper cell and T regulatory cell (Treg) inflammatory response. Prolonged T helper 2 biased immune responses in lymphedema regulate the pathology of this disease by promoting tissue fibrosis, inhibiting formation of collateral lymphatics, decreasing lymphatic vessel pumping capacity, and increasing lymphatic leakiness. Treg infiltration following lymphatic injury results from proliferation of natural Tregs and suppresses innate and adaptive immune responses. These studies have broad clinical relevance since understanding how lymphatic injury in lymphedema can modulate immune responses may provide a template with which we can study more subtle forms of lymphatic injury that may occur in physiologic conditions such as aging, obesity, metabolic tumors, and in the tumor microenvironment.

3D Immunocompetent Organ‐on‐a‐Chip Models

“…[ 13 ] Structural and functional abnormalities of the components of the lymphatic system can contribute to various diseases, including immune disorders, cancer, and lymphedema, among others. [ 74–77 ] Despite advances toward understanding the structures and functions of the lymphatic system, promising tools and technologies are needed to study its role in pathophysiology of various diseases as well as to develop immunotherapeutics. To this end, a microfluidic chip device of the paracortical region of the lymph node was developed to investigate the dynamic interactions between DCs and T cells under shear stress.…”

The Role of Lymphatic Vascular Function in Metabolic Disorders

“…The observation that increased inflammation associated with obesity is correlated with lymphatic dysfunction and reduced vessel density may seem contradictory provided that several studies have shown that under an inflammatory environment, lymphangiogenesis is stimulated as a mechanism for antigen clearance and inflammation resolution in response to prolymphangiogenic factors, such as VEGF-C, VEGF-D, and VEGF-A, that are secreted from infiltrating macrophages that respond to chemoattractants expressed by LECs (Kataru et al, 2009;Rahier et al, 2011;Kim et al, 2014). However, other studies have demonstrated that anti-lymphangiogenic cytokines, including IFN-γ and TGF-β1 (Shao and Liu, 2006;Clavin et al, 2008;Oka et al, 2008;Kataru et al, 2011), are elevated in chronic inflammatory responses (Zampell et al, 2012b;Savetsky et al, 2015b;Shin et al, 2015;Kataru et al, 2019) and elevated IFN-γ and TGF-β1 levels were previously detected in obese mice (Winer et al, 2009;Hespe et al, 2016). Additionally, elevated TGF-β1 levels and BMI were observed to have significant partial correlation in human subjects (Yadav et al, 2011).…”

Emerging Roles of Mast Cells in the Regulation of Lymphatic Immuno-Physiology

“…In addition, novel studies suggest that inflammation-induced changes to the microenvironment can upregulate the expression of adhesion molecules such as ICAM-1 and VCAM-1, as well as chemokines such as CCL21 and CX3CL1 in lymphatic endothelial cells (LECs) (148,149). This upregulation can enhance trafficking of antigen-presenting cells, such as DCs and macrophages, from the affected tissues through the walls of collecting LVs toward the draining lymph node, thus contributing to the resolution of tissue inflammation (145,146,150). In addition, molecules such as the chemokine scavenging receptor D6 expressed by LECs can selectively regulate the interaction between mature and immature DCs, which helps in the cellular trafficking and removal of inflammatory chemokines.…”