Abstract
Lymphangiogenesis is a common phenomenon observed during inflammation and engraftment of transplants, but its precise role in the immune response and underlying mechanisms of regulation remain poorly defined. Here we showed that in response to injury and autoimmunity, lymphangiogenesis occurred around islets and played a key role in the islet inflammation in mice. Vascular endothelial growth factors receptor 3 (VEGFR3) is specifically involved in lymphangiogenesis, and blockade of VEGFR3 potently inhibited lymphangiogenesis in both islets and the draining LN during multiple low-dose streptozotocin (MLDS) induced autoimmune insulitis, which resulted in less T cell infiltration, preservation of islets and prevention of the onset of diabetes. In addition to their well-known conduit function, lymphatic endothelial cells (LEC) also produced chemokines in response to inflammation. These LEC attracted two distinct CX3CR1hi and LYVE-1+ macrophage subsets to the inflamed islets and CX3CR1hi cells were influenced by LEC to differentiate into LYVE-1+ cells closely associated with lymphatic vessels. These observations indicate a linkage among lymphangiogenesis and myeloid cell inflammation during insulitis. Thus, inhibition of lymphangiogenesis holds potential for treating insulitis and autoimmune diabetes.
Highlights
Lymphatics undergo growth and remodeling during many pathophysiological processes [1,2,3,4,5], and contribute to immunity during tumor growth and metastases [1,2]
Since sunitinib can inhibit kinases involved in blood vascular angiogenesis, this showed that sunitinib prevented islet inflammation mainly through inhibiting lymphangiogenesis
We found that lymphangiogenesis played a pivotal role in multiple low-dose streptozotocin (MLDS) induced islet inflammation and autoimmune insulitis
Summary
Lymphatics undergo growth and remodeling during many pathophysiological processes [1,2,3,4,5], and contribute to immunity during tumor growth and metastases [1,2]. Studies in NOD mice show that lymphatic vessels are adjacent to inflamed islets [7,8] and a functional lymphatic network is found in transplanted islets [9], suggesting peri- and intra-islet lymphatics might be involved in regulating islet inflammation. Vascular endothelial growth factors VEGF-C and -D are the most potent inducers of lymphatic growth via VEGFR3 [13,14,17,18]. A recent study showed that both VEGFR2 and VEGFR3 mediate VEGF-A induced inflammatory cutaneous lymphangiogenesis [20]. Lymphangiogenesis can be inhibited by VEGF-C/-D trap, neutralizing anti-VEGFR3 antibodies, or tyrosine kinase inhibitors, such as sunitinib, which inhibit VEGFR3 signaling [21]
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