Class 3 semaphorins induce F-actin reorganization in human dendritic cells: Role in cell migration

Abstract

Class 3 semaphorins (Semas) are soluble proteins that are well recognized for their role in guiding axonal migration during neuronal development. In the immune system, Sema3A has been shown to influence murine dendritic cell (DC) migration by signaling through a neuropilin (NRP)-1/plexin-A1 coreceptor axis. Potential roles for class 3 Semas in human DCs have yet to be described. We tested the hypothesis that Sema3A, -3C, and -3F, each with a unique NRP-1 and/or NRP-2 binding specificity, influence human DC migration. In this report, we find that although NRP-1 and NRP-2 are expressed in human immature DCs (imDCs), NRP-2 expression increases as cells mature further, whereas expression of NRP-1 declines dramatically. Elevated levels of RNA encoding plexin-A1 and -A3 are present in both imDCs and mature DC (mDCs), supporting the relevance of Sema/NRP/plexin signaling pathways in these cells. Sema3A, -3C, and -3F bind to human DCs, with Sema3F binding predominantly through NRP-2. The binding of these Semas leads to reorganization of actin filaments at the plasma membrane and increased transwell migration in the absence or presence of chemokine CCL19. Microfluidic chamber assays failed to demonstrate consistent changes in speed of Sema3C-treated DCs, suggesting increased cell deformability as a possible explanation for enhanced transwell migration. Although monocytes express RNA encoding Sema3A, -3C, and -3F, only RNA encoding Sema3C increases robustly during DC differentiation. These data suggest that Sema3A, -3C, and -3F, likely with coreceptors NRP-1, NRP-2, and plexin-A1 and/or -A3, promote migration and possibly other activities of human DCs during innate and adaptive immune responses.

Opposing Effects of Neuropilin-1 and -2 on Sensory Nerve Regeneration in Wounded Corneas: Role of Sema3C in Ameliorating Diabetic Neurotrophic Keratopathy

“…Considering that the level of SEMA3A was elevated in DM wounded CECs compared with DM nonwounded CECs, we postulate that the formation of NRP1/2 dimers, which are lacking in diabetic and/or NRP1-neutralized CECs, is most effective for transducing SEMA3C signals into healing corneal epithelia. This is supported by findings that SEMA3C has maximal affinity for NRP1/2 heterodimers (35) and that NRP2 neutralization only reduced 50% of SEMA3C binding to the surface of dendritic cells, which express both NRP isoforms during differentiation (37). Hence, we propose that defects in SEMA3C-NRP1/2 signaling is partially responsible for decreased reepithelialization in DM corneas.…”

Integrated High Throughput Analysis Identifies GSK3 as a Crucial Determinant of p53-Mediated Apoptosis in Lung Cancer Cells

“…An inactive version of the p53 protein is expressed in various cancers, which has given rise to the idea of using p53 re-activation to combat these cancers [13]. Profound in vivo suppression of various types of established tumours via p53 re-activation, without affecting normal tissues, was demonstrated by three independent studies in 2006 and 2007, supporting the idea that pharmacological p53 restoration may be an effective means of treating cancer [14-16]. According to the National Cancer Institute database, more than 150 clinical trials involving p53 are currently ongoing [17].…”

Endothelial Semaphorin 3F Maintains Endothelial Barrier Function and Inhibits Monocyte Migration

“…SEMA3A has been shown to inhibit migration of monocytes [15,42] and for SEMA3E it has been shown that it can inhibit the migration of macrophages [44] and neutrophils [43]. Only for mature dendritic cells there have been reports that SEMA3A, -C and -F can promote their migration [45]. For SEMA3F the functional effect on leukocyte migration had not been fully studied.…”