Inflammation and Lymphedema Are Exacerbated and Prolonged by Neuropilin 2 Deficiency

Abstract

The vasculature influences the progression and resolution of tissue inflammation. Capillaries express vascular endothelial growth factor (VEGF) receptors, including neuropilins (NRPs), which regulate interstitial fluid flow. NRP2, a receptor of VEGFA and semaphorin (SEMA) 3F ligands, is expressed in the vascular and lymphatic endothelia. Previous studies have demonstrated that blocking VEGF receptor 2 attenuates VEGFA-induced vascular permeability. The inhibition of NRP2 was hypothesized to decrease vascular permeability as well. Unexpectedly, massive tissue swelling and edema were observed in Nrp2 À/À mice compared with wild-type littermates after delayed-type hypersensitivity reactions. Vascular permeability was twofold greater in inflamed blood vessels in Nrp2-deficient mice compared to those in Nrp2-intact littermates. The addition of exogenous SEMA3F protein inhibited vascular permeability in Balb/cJ mice, suggesting that the loss of endogenous Sema3F activity in the Nrp2-deficient mice was responsible for the enhanced vessel leakage. Functional lymphatic capillaries are necessary for draining excess fluid after inflammation; however, Nrp2-mutant mice lacked superficial lymphatic capillaries, leading to 2.5-fold greater fluid retention and severe lymphedema after inflammation. In conclusion, Nrp2 deficiency increased blood vessel permeability and decreased lymphatic vessel drainage during inflammation, highlighting the importance of the NRP2/SEMA3F pathway in the modulation of tissue swelling and resolution of postinflammatory edema. (Am J Pathol 2016 http://dx

The intragraft microenvironment as a central determinant of chronic rejection or local immunoregulation/tolerance

“…Furthermore, members of these families are increasingly being appreciated as modulators of cell mediated immune responses, vascular disease and alloimmunity due to high expression levels of their receptors on leukocyte subsets [70–73] and EC [74–78]. Below, we wish to briefly discuss the class 3 semaphorin family (SEMA3) that have potential to regulate the alloimmune response [72,73,79].…”

“…Over the past 10 years, several studies have identified SEMA3 receptors, including neuropilin (NRP)-1, NRP-2 and Plexin A family molecules on tumor cells suggesting that they function within the tumor microenvironment to limit cellular migration and growth [80,81,84,85]. Three members of the Class 3 family (SEMA3A, -3C and -3F) also bind NRP’s that are expressed on immune cell types including EC [75–78,81], antigen presenting cells [86,87] and CD4 + T cells [70]. In general, ligation of the NRP receptor alone is not sufficient to elicit a signal, but serves as co-receptor to activate Plexin A family receptors that in turn elicit potent inhibitory signaling responses [88,89].…”

“…Within EC, SEMA3-NRP-2 interactions are anti-angiogenic, and stabilize the microvasculature and inhibit vascular leak in association with cell mediated immunity [77,78,84]. Mucka et al observed massive tissue swelling and edema in NRP-2 knockout mice compared with wild-type littermates in association with delayed-type hypersensitivity [78]. They also demonstrated that the injection of SEMA3F into skin was potent to inhibit vascular leak induced by VEGF.…”

NRP2 as an emerging angiogenic player; promoting endothelial cell adhesion and migration by regulating recycling of α5 integrin

“…Based on early transgenic mouse studies in this field, it was originally speculated that NRP1 is mainly expressed on arteries, arterioles and capillaries, whereas NRP2 is expressed on veins, venules and lymphatic vessels [9], [10]. However, subsequent studies have revealed that both NRPs are expressed in normal blood and lymphatic endothelial cells, and both play essential roles in forming blood and lymphatic vasculature networks [11], [12], [13]. Despite this, investigations into elucidating the roles of endothelial NRPs during angiogenesis have, for the most part, focused on NRP1 [3].…”

Immunomodulatory Functions of Neuronal Guidance Proteins

“…This action of NRP-1 could be used in the future for the treatment of sepsis, since Gao et al were able to show that the NRP-1 agonist tuftsin improved sepsis survival through a reduction of Treg-induced immunosuppression [45,46]. Neuropilin 2 (NRP-2) protects the vascular barrier and increases lymphatic drainage during acute inflammation through endogenous Sema3F [47]. This demonstrates the growing recognition of the role of neuropilins in the regulation of acute inflammatory conditions.…”