Lymphangiogenesis: fuel, smoke, or extinguisher of inflammation's fire?

Abstract

Lymphangiogenesis is a recognized hallmark of inflammatory processes in tissues and organs as diverse as the skin, heart, bowel, and airways. In clinical and animal models wherein the signaling processes of lymphangiogenesis are manipulated, most studies demonstrate that an expanded lymphatic vasculature is necessary for the resolution of inflammation. The fundamental roles that lymphatics play in fluid clearance and immune cell trafficking from the periphery make these results seemingly obvious as a mechanism of alleviating locally inflamed environments: the lymphatics are simply providing a drain. Depending on the tissue site, lymphangiogenic mechanism, or induction timeframe, however, evidence shows that inflammation-associated lymphangiogenesis (IAL) may worsen the pathology. Recent studies have identified lymphatic endothelial cells themselves to be local regulators of immune cell activity and its consequential phenotypes - a more active role in inflammation regulation than previously thought. Indeed, results focusing on the immunocentric roles of peripheral lymphatic function have revealed that the basic drainage task of lymphatic vessels is a complex balance of locally processed and transported antigens as well as interstitial cytokine and immune cell signaling: an interplay that likely defines the function of IAL. This review will summarize the latest findings on how IAL impacts a series of disease states in various tissues in both preclinical models and clinical studies. This discussion will serve to highlight some emerging areas of lymphatic research in an attempt to answer the question relevant to an array of scientists and clinicians of whether IAL helps to fuel or extinguish inflammation. Impact statement Inflammatory progression is present in acute and chronic tissue pathologies throughout the body. Lymphatic vessels play physiological roles relevant to all medical fields as important regulators of fluid balance, immune cell trafficking, and immune identity. Lymphangiogenesis is often concurrent with inflammation and can potentially aide or worsen disease progression. How new lymphatic vessels impact inflammation and by which mechanism is an important consideration in current and future clinical therapies targeting inflammation and/or vasculogenesis. This review identifies, across a range of tissue-specific pathologies, the current understanding of inflammation-associated lymphangiogenesis in the progression or resolution of inflammation.

Keywords: Vascular endothelial growth factor receptor-3; endometriosis; hypertension; lymphatic; metabolic syndrome; vascular endothelial growth factor-D.

Figure 1

Expansion of the renal lymphatic network. Lymphatic vessels are few in the murine renal cortex limited to tracking along interlobular arterioles (arrow, left). Overexpression of VEGF-D (right) by tubular epithelial cells induces a massive expansion of cortical lymphatic vessels (green, LYVE-1) providing a model to study the impact of lymphatic density in renal function and pathology. “A” indicates arteriole. “G” indicate glomeruli. Blue = DAPI. Scale bars = 50 µm. VEGF-D: vascular endothelial growth factor-D

Figure 2

Adipose tissue lymphangiogenesis. Obese murine inguinal adipose tissue lacks lymphatic capillaries (green, LYVE1) and contains macrophages formed crown-like structures (red, Mac2; arrows highlight some) in the inflamed tissue (left). VEGF-D overexpression induces lymphangiogenesis in adipose tissue (right), with IAL potentially providing a route for immune efflux with fewer Mac2+ areas (arrows, all noted) in equally obese adipose tissue. Blue = DAPI. Scale bars = 100 µm. VEGF-D: vascular endothelial growth factor-D

Figure 3

Inflammation-associated lymphangiogenesis (IAL) and the modulation of tissue homeostasis. Normal, functional lymphatics clear fluid, macromolecules, and immune cells – both passively and actively – from the peripheral interstitium. Trafficking to the afferent lymph node allows for the propagation of specific immune responses. When lymphatics are deficient (left), as in lymphedema, failed clearance leads to chronic inflammation. With IAL in inflammation, an increased functional lymphatic network permits resolution as fluid and cytokines are cleared and leukocytes – activated locally by inflammation or through contact with lymphatic endothelial cells (LEC) – traffic to the lymph node. Disorganized lymphatic expansion in inflammation, however, results in lymph efflux, or “leakiness” of hyperplastic vessel (right). This reduced functional capacity fails to aid, and indeed can propagate, inflammation