Semaphorin3E/plexinD1 Axis in Asthma: What We Know So Far!

Semaphorin3E belongs to the large family of semaphorin proteins. Semaphorin3E was initially identified as axon guidance cues in the neural system. It is universally expressed beyond the nervous system and contributes to regulating essential cell functions such as cell migration, proliferation, and adhesion. Binding of semaphorin3E to its receptor, plexinD1, triggers diverse signaling pathways involved in the pathogenesis of various diseases from cancer to autoimmune and allergic disorders. Here, we highlight the novel findings on the role of semaphorin3E in airway biology. In particular, we highlight our recent findings on the function and potential mechanisms by which semaphorin3E and its receptor, plexinD1, impact airway inflammation, airway hyperresponsiveness, and remodeling in the context of asthma.

Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner.

Semaphorin (Sema)4A is a transmembrane glycoprotein that is elevated in several autoimmune diseases such as systemic sclerosis, rheumatoid arthritis and multiple sclerosis. Sema4A has a key role in the regulation of Thelper Th1 and Th2 differentiation and we recently demonstrated that CD4+ T cell activation induces the expression of Sema4A. However, the autocrine role of Sema4A on Th cell differentiation remains unknown. Naïve Th cells from healthy controls were cell sorted and differentiated into Th1, Th2 and Th17 in the presence or absence of a neutralizing antibody against the Sema4A receptor PlexinD1. Gene expression was determined by quantitative PCR and protein expression by ELISA and flow cytometry. We found that the expression of Sema4A is induced during Th1, Th2 and Th17 differentiation. PlexinD1 neutralization induced the differentiation of Th1 cells, while reduced the Th2 and Th17 skewing. These effects were associated with an upregulation of the transcription factor T-bet by Th1 cells, and to downregulation of GATA3 and RORγt in Th2 cells and Th17 cells, respectively. Finally, PlexinD1 neutralization regulates the systemic sclerosis patients serum-induced cytokine production by CD4+ T cells. Therefore, the autocrine Sema4A-PlexinD1 signaling acts as a negative regulator of Th1 skewing but is a key mediator on Th2 and Th17 differentiation, suggesting that dysregulation of this axis might be implicated in the pathogenesis of CD4+ T cell-mediated diseases.

Patterning mechanisms of the sub-intestinal venous plexus in zebrafish.

Despite considerable interest in angiogenesis, organ-specific angiogenesis remains less well characterized. The vessels that absorb nutrients from the yolk and later provide blood supply to the developing digestive system are primarily venous in origin. In zebrafish, these are the vessels of the Sub-intestinal venous plexus (SIVP) and they represent a new candidate model to gain an insight into the mechanisms of venous angiogenesis. Unlike other vessel beds in zebrafish, the SIVP is not stereotypically patterned and lacks obvious sources of patterning information. However, by examining the area of vessel coverage, number of compartments, proliferation and migration speed we have identified common developmental steps in SIVP formation. We applied our analysis of SIVP development to obd mutants that have a mutation in the guidance receptor PlexinD1. obd mutants show dysregulation of nearly all parameters of SIVP formation. We show that the SIVP responds to a unique combination of pathways that control both arterial and venous growth in other systems. Blocking Shh, Notch and Pdgf signaling has no effect on SIVP growth. However Vegf promotes sprouting of the predominantly venous plexus and Bmp promotes outgrowth of the structure. We propose that the SIVP is a unique model to understand novel mechanisms utilized in organ-specific angiogenesis.

PlexinD1 is required for proper patterning of the periocular vascular network and for the establishment of corneal avascularity during avian ocular development.

The anterior eye is comprised of an avascular cornea surrounded by a dense periocular vascular network and therefore serves as an excellent model for angiogenesis. Although signaling through PlexinD1 underlies various vascular patterning events during embryonic development, its role during the formation of the periocular vascular network is yet to be determined. Our recent study showed that PlexinD1 mRNA is expressed by periocular angioblasts and blood vessels during ocular vasculogenesis in patterns that suggest its involvement with Sema3 ligands that are concurrently expressed in the anterior eye. In this study, we used in vivo knockdown experiments to determine the role of PlexinD1 during vascular patterning in the anterior eye of the developing avian embryos. Knockdown of PlexinD1 in the anterior eye caused mispatterning of the vascular network in the presumptive iris, which was accompanied by lose of vascular integrity and profuse hemorrhaging in the anterior chamber. We also observed ectopic vascularization of the cornea in PlexinD1 knockdown eyes, which coincided with the formation of the limbal vasculature in controls. Finally we show that Sema3E and Sema3C transcripts are expressed in ocular tissue that is devoid of vasculature. These results indicate that PlexinD1 plays a critical role during vascular patterning in the iris and limbus, and is essential for the establishment of corneal avascularity during development. We conclude that PlexinD1 is involved in vascular response to antiangiogenic Sema3 signaling that guides the formation of the iris and limbal blood vessels by inhibiting VEGF signaling.

Neuronal chemorepellent Semaphorin 3E inhibits human airway smooth muscle cell proliferation and migration.

BACKGROUND: Chronic airway diseases, including asthma, are characterized by increased airway smooth muscle (ASM) mass that is due in part to growth factor-mediated ASM cell proliferation and migration. However, the molecular mechanisms underlying these effects are not completely understood. Semaphorin 3E (Sema3E) has emerged as an essential mediator involved in cell migration, proliferation, and angiogenesis, although its role in ASM cell function is not investigated. OBJECTIVES: We sought to determine the expression of Sema3E receptor, plexinD1, in human ASM cells (HASMCs); effect of Sema3E on basal and platelet-derived growth factor (PDGF)-induced proliferation and migration; and underlying signaling pathways. METHODS: Expression of plexinD1 in HASMCs was studied with RT-PCR, immunostaining, and flow cytometry. The effect of Sema3E on HASMC proliferation and migration was evaluated by 5-ethynyl-2'-deoxyuridine (EdU) incorporation, cell count, and Boyden chamber assay. Sema3E-mediated intracellular signaling was investigated with fluorescent microscopy, flow cytometry, Rac1 activation, and Western blot analysis. RESULTS: HASMCs from healthy persons expressed plexinD1 more than HASMCs from asthmatic patients. Sema3E increased plexinD1 expression in HASMCs from asthmatic patients. Recombinant Sema3E inhibited PDGF-mediated HASMC proliferation and migration, which was associated with F-actin depolymerization, suppression of PDGF-induced Rac1 guanosine triphosphatase activity, and Akt and extracellular signal-regulated kinase 1 and 2 phosphorylation. Bronchial biopsies from patients with mild asthma displayed immunoreactivity of plexinD1, suggesting the potential in vivo role of Sema3E-PlexinD1 axis in HASMC function. CONCLUSION: This study provides the first evidence that Sema3E receptor is expressed and plays functional roles in HASMCs. Our data suggest a regulatory role of Sema3E in PDGF-mediated proliferation and migration, leading to downregulation of ASM remodeling.

Plexin D1 emerges as a novel target in the development of neural lineage plasticity in treatment-resistant prostate cancer.

Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 is highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression is associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibit neural lineage pathways, suppressing NEPC cell proliferation, PDX tumor organoid viability, and xenograft tumor growth. Mechanistically, the chaperone protein HSP70 regulates PLXND1 protein stability through degradation, and inhibition of HSP70 decreases PLXND1 expression and NEPC organoid growth. In summary, our findings suggest that PLXND1 could be a new therapeutic target and molecular indicator for NEPC.

Sema-3E/PlexinD1 axis modulates dendritic cell phenotypes and functions: Current status and future implications.

This comprehensive research review explores the complex interplay between the Sema-3E/PlexinD1 axis and dendritic cells (DCs), highlighting its critical role in immune modulation with implications for clinical application Critical regulators of immune responses Dendritic cells are central to adaptive immunity, and the Sema-3E /PlexinD1 axis emerges as a key modulator affecting their phenotypes and functions Review delineates the impact of this signaling axis on DC maturation, migration, antigen presentation, and cytokine production, unravels its multifaceted role in shaping the immune response. Recognizing the limitations and gaps in current knowledge, the study highlights the need for further studies to condition downstream signaling events and related information experienced by the Sema-3E/PlexinD1 axis emphasizes the clarity of the immune system. The review concludes by identifying opportunities for translation, focusing on therapeutic and diagnostic potential. It highlights the importance of collaborative, interdisciplinary efforts to address the challenges and harness the therapeutic and pathological potential of targeting the Sema-3E/PlexinD1 axis, thus opening the way for transformative advances in immunology and clinical medicine.

Plxnd1-mediated mechanosensing of blood flow controls the caliber of the Dorsal Aorta via the transcription factor Klf2.

The cardiovascular system generates and responds to mechanical forces. The heartbeat pumps blood through a network of vascular tubes, which adjust their caliber in response to the hemodynamic environment. However, how endothelial cells in the developing vascular system integrate inputs from circulatory forces into signaling pathways to define vessel caliber is poorly understood. Using vertebrate embryos and in vitro-assembled microvascular networks of human endothelial cells as models, flow and genetic manipulations, and custom software, we reveal that Plexin-D1, an endothelial Semaphorin receptor critical for angiogenic guidance, employs its mechanosensing activity to serve as a crucial positive regulator of the Dorsal Aorta's (DA) caliber. We also uncover that the flow-responsive transcription factor KLF2 acts as a paramount mechanosensitive effector of Plexin-D1 that enlarges endothelial cells to widen the vessel. These findings illuminate the molecular and cellular mechanisms orchestrating the interplay between cardiovascular development and hemodynamic forces.

NK/DC crosstalk-modulating antitumor activity via Sema3E/PlexinD1 axis for enhanced cancer immunotherapy.

The complex relationship between natural killer (NK) cells and dendritic cells (DCs) within the tumor microenvironment significantly impacts the success of cancer immunotherapy. Recent advancements in cancer treatment have sought to bolster innate and adaptive immune responses through diverse modalities, aiming to tilt the immune equilibrium toward tumor elimination. Optimal antitumor immunity entails a multifaceted interplay involving NK cells, T cells and DCs, orchestrating immune effector functions. Although DC-based vaccines and NK cells' cytotoxic capabilities hold substantial therapeutic potential, their interaction is frequently hindered by immunosuppressive elements such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells. Chemokines and cytokines, such as CXCL12, CCL2, interferons, and interleukins, play crucial roles in modulating NK/DC interactions and enhancing immune responses. This review elucidates the mechanisms underlying NK/DC interaction, emphasizing their pivotal roles in augmenting antitumor immune responses and the impediments posed by tumor-induced immunosuppression. Furthermore, it explores the therapeutic prospects of restoring NK/DC crosstalk, highlighting the significance of molecules like Sema3E/PlexinD1 in this context, offering potential avenues for enhancing the effectiveness of current immunotherapeutic strategies and advancing cancer treatment paradigms. Harnessing the dynamic interplay between NK and DC cells, including the modulation of Sema3E/PlexinD1 signaling, holds promise for developing more potent therapies that harness the immune system's full potential in combating cancer.

Targeting the Semaphorin3E-plexinD1 complex in allergic asthma.

Asthma is a heterogenous airway disease characterized by airway inflammation and remodeling. It affects more than 300 million people worldwide and poses a significant burden on society. Semaphorins, discovered initially as neural guidance molecules, are ubiquitously expressed in various organs and regulate multiple signaling pathways. Interestingly, Semaphorin3E is a critical molecule in lung pathophysiology through its role in both lung development and homeostasis. Semaphorin3E binds to plexinD1, mediating regulatory effects on cell migration, proliferation, and angiogenesis. Recent in vitro and in vivo studies have demonstrated that the Semaphorin3E-plexinD1 axis is implicated in asthma, impacting inflammatory and structural cells associated with airway inflammation, tissue remodeling, and airway hyperresponsiveness. This review details the Semaphorin3E-plexinD1 axis in various aspects of asthma and highlights future directions in research including its potential role as a therapeutic target in airway allergic diseases.