|Year : 2022 | Volume
| Issue : 4 | Page : 189-195
Semaphorin-3E/plexinD1 axis in allergic asthma
Mojdeh Matloubi, Amena Aktar, Lianyu Shan, Latifa Koussih, Abdelilah S Gounni
Department of Immunology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
|Date of Submission||06-May-2022|
|Date of Decision||12-Jul-2022|
|Date of Acceptance||31-Jul-2022|
|Date of Web Publication||23-Sep-2022|
Dr. Abdelilah S Gounni
Department of Immunology, 471 Apotex Centre 750 McDermot Avenue, University of Manitoba, Winnipeg, MB R3E 0T5
Source of Support: None, Conflict of Interest: None
Semaphorins are cell-membrane bound or secretory proteins that regulate cell migration, differentiation, proliferation, and morphology. Semaphorins are guidance cues that have either repulsive or attractive effects on growth cones and thus determine their direction toward or away from a target place. Moreover, they act as either chemorepellent or attractive molecules in other systems. Semaphorins were initially discovered as axon guidance molecules essential in nervous system development. However, growing evidence shows that they have a crucial role in other systems, including the immune, cardiovascular, and respiratory systems. This review highlights the immunoregulatory effects of semaphorin 3E in allergic airway inflammation.
Keywords: Allergic asthma, inflammation, neuropilins, plexins, semaphorin
|How to cite this article:|
Matloubi M, Aktar A, Shan L, Koussih L, Gounni AS. Semaphorin-3E/plexinD1 axis in allergic asthma. Adv Biomed Health Sci 2022;1:189-95
| Background|| |
The first semaphorin was discovered in 1993, initially in the collapsin family. The semaphorin family was later expanded due to the discovery of new proteins that have similarities or homology in their amino acid sequence and structure [1,2]. More than 20 semaphorins have been identified and divided into eight classes based on their amino acid component and structural similarity [3,4]. Classes 1 and 2 are found in invertebrates, classes 3–7 are found in vertebrates, and class V (sema-8) is restricted to viruses . According to their localization, they have been divided into other categories. Semaphorin classes 1, 4, 5, and 6 are membrane-bound proteins, classes 2, 3, and 8 are secreted proteins, and class 7 is glycosyl-phosphatidyl-inositol (GPI)-linked proteins  [Figure 1].
|Figure 1: Semaphorins family. Semaphorins are categorized into eight classes. Class 1 and 2 semaphorins are identified in invertebrates. Class 3–7 semaphorins are found in vertebrates. Class V (Sema-8) is found in the virus. All semaphorins share a conserved region named the Sema domain. Semaphorins 2, 3, and 8 are secretory proteins, whereas classes 1, 4, 5, 6, and 7 are membrane-bound proteins. Some semaphorins (classes 2, 3, 4, and 7) have immunoglobulin (Ig)-like domain, whereas class 5 has a thrombospondin domain. Class 7 semaphorin is a membrane-associated GPI linked by its carboxyl terminus.|
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Semaphorins are made up of different domains. The first extracellular domain is called the “Sema domain,” consisting of around 500 amino acids conserved among semaphorin proteins [7,8]. The Sema domain mainly regulates semaphorin activities. The following domain, which is tightly coupled with the Sema domain, is the cysteine-rich domain called PSI (plexin, semaphorin, and integrins) domain. The ectodomain of classes 1 and 6 consists of Sema domain and PSI domain. Some have another domain called immunoglobulin (Ig)-like domain or thrombospondin domain. The Ig-like domain is present in semaphorin classes 2, 3, 4, 5, and 7, whereas thrombospondin is only present in class 5 . Some semaphorins (class 3) undergo proteolytic cleavage to produce an active form ,,, [Figure 1].
| II-SEMAPHORIN RECEPTORS|| |
Semaphorins transmit their signals into the cells through two main receptors: plexins and neuropilins [13,14]. Most of the semaphorin molecules mediate their signal through plexins alone. However, semaphorins class 3, except semaphorin3E (Sema3E), mediate their signal through the combination of plexins and neuropilins. They need co-receptor neuropilins with plexins to transmit the signal properly [15,16]. Moreover, semaphorin molecules can transmit their signals through other receptors. These include CD72, T-cell immunoglobulin and mucin domain-containing protein-2 (TIM-2), heparan sulfate proteoglycan (HSPG), and chondroitin sulfate proteoglycans [5,14]. Furthermore, different proteins, including G-coupled proteins, tyrosine kinase, GTPase, and other adhesion molecules, are involved in their signal process .
| Neuropilins|| |
In addition to plexins, several other transmembrane receptors act as co-receptors for semaphorins . The well-described co-receptor of plexins is neuropilins. There are two types of neuropilins documented: neuropilin-1 (NRP-1) and neuropilin-2 (NRP-2). The extracellular part of neuropilins contains two CUB domains named a1 and a2 domain, two coagulation factor V/VIII homology domains called b1 and b2 domain, and an MAM domain called c domain . Vascular endothelial growth factor (VEGF) binds to the b1 and b2 domains, whereas semaphorin class 3, except Sema3E, binds to a1 and a2 domains, thereby activating vascular endothelial growth factor receptor (VEGFR) and plexins . The MAM domain is responsible for the dimerization of the neuropilins. These transmembrane receptors have a short cytoplasmic tail. As a result, they cannot transmit signals into the cells alone and therefore act as a co-receptor of another ligand. For instance, semaphorins class 3 use neuropilins to activate plexin A for axon guidance, and VEGF uses the NRP-1 as a co-receptor to activate VEGFR-2 on endothelial cells (ECs) [14,18].
| Plexins|| |
Most semaphorins mediate their function through plexin receptors. Plexins are single-pass, a group of nine transmembrane proteins [19,20]. They are categorized into four classes, including A, B, C, and D. All four classes of plexins play a vital role in transmitting signal into cells. These plexins include class A (Plexin-A1, A2, A3, A4), class B (Plexin-B1, B2, B3), class C (PlexinC1), and class D (PlexinD1), whereas only Plexin-A and Plexin-B play a role in invertebrate .
The overall structure of all plexins is quite similar between members. The extracellular portion of plexins contains around 500 amino acid Sema domains followed by cysteine-rich PSI (plexin-semaphorin-integrin) domain and three IPT (immunoglobulin-plexin-transcription factors) domain [7,22]. The difference between the plexin’s Sema domain and one of the semaphorins is that the former does not dimerize . Sema domain acts as a ligand-binding domain, whereas the PSI domain is essential for protein–protein interaction, and the IPT domain is critical for perfect ligand binding ,,. The Sema domain acts as an autoinhibitory domain, thereby constraining the activation of plexins in the absence of ligand .
The cytoplasmic domain of plexins plays a critical role in the transduction of the signal after ligand binding . The cytoplasmic domain does not have kinase activity; however, it can be tyrosine phosphorylated by receptor or non-receptor tyrosine kinase, which indicates that plexins transduce the signal into the cytoplasm by associating a tyrosine kinase . The GTPase-binding domain and GTPase-activating protein (GAP) domain are highly conserved regions of the cytoplasmic tail of plexin receptors. These domains play a critical role and regulate many responses upon activation .
Different plexins bind to various semaphorins with specificity. For instance, membrane-bound class 5 and class 6 semaphorins directly activate class A plexins, whereas secreted class 3 semaphorins, except Sema3E, require neuropilins as co-receptors to stabilize the semaphorin–plexin interaction [10,18]. Semaphorins class 4 and 5 activate class B plexins, and class 7A semaphorins activate plexin C1. Several proteins of class 3 semaphorins bind to plexinD1 in a neuropilin-dependent manner, whereas Sema3E and Sema4A can bind to plexinD1 independently of neuropilins [10,20].
| PLEXIND1|| |
PlexinD1 is considered the most structurally diverse protein among the four classes of plexins. PlexinD1 is expressed by different cells, including neuron cells, endothelium, airway smooth muscle (ASM) cell, fat cell, thymocytes, activated B cells, dendritic cells (DCs), neutrophils, and macrophage [10,27-30].
Mature plexinD1 consists of 1879 amino acids with 208 kDa molecular mass . Extracellular part N-terminal contains Sema domain, three MRS (MET-related sequence) or PSI repeats, four IPT domains, and a transmembrane (TM) domain. The cytoplasmic portion of the plexinD1 is called Sex and Plexins (SP) domain. It has a GTPase-activating protein (GAP) domain. This GAP domain consists of two highly conserved regions C1 and C2. A Rho-GTPase-binding domain (RBD) is present between C1 and C2 regions. Ras GAP motif 1 (RasGAP1) and Ras GAP motif 2 (RasGAP2) are in the C1 and C2 regions, respectively. Each of the motifs contains conserved arginine residues required for inhibiting the activity of the R-Ras protein. After the GAP domain, the C-terminal of plexinD1 has a terminal segment (T-segment) linked to a short PDZ-binding motif (D1-PBM). T-segment is highly conserved among members of the same plexins subfamily [Figure 2] .
|Figure 2: Structure of plexinD1, including active and inactive states. The extracellular N-terminal part contains a sema domain, where Sema3E binds. After the sema domain, there are three MRS (MET-related sequence), also called PSI (plexin, semaphorin, and integrins), repeats, four IPT (immunoglobin-like fold shared by plexins and transcription factors) domains, and the transmembrane domain (TM). The cytosolic portion of plexinD1 contains a GTPase activating protein (GAP) domain with two highly conserved C1 and C2 regions. The C1 region contains a Ras GAP motif-1 (RasGAP1), and C1 region has RasGAP2. A Rho-GTPase-binding domain (RBD) is located between the C1 and C2 regions. The GAP domain is followed by a short C-terminal region named the terminal (T) segment. PDZ-binding motif (D1-PBM) is the end of plexinD1 connected to the T-segment. In the absence of Sema ligands, plexinD1 remains in a conformationally inactive folded state and non-functional. Upon Sema3E binding with Sema domain of plexinD1, it goes to conformational changes that activate its GAP domain and downstream signals.|
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Activation of PlexinD1
PlexinD1 has two states: inactive and active state. In the absence of ligand, plexinD1 remains inactive. The Sema domain is folded into the rest of the extracellular domain, and intracellular C1 and C2 regions of the GAP domain are wrapped around each other [Figure 2]. Sema3E is a canonical ligand of plexinD1. Upon binding of Sema3E to Sema domain of plexinD1, a conformational change of plexinD1 occurs that activates the GAP domain . Activation of the cytoplasmic tail of plexinD1 is involved in different cellular processes, including integrin-mediated cell adhesion, cell proliferation, cell–cell junction, and establishment of cell polarity . For instance, in an inactive form, GTP-bound Rnd2 binds to RBD, preventing the binding of active GTP-bound Ras and Rac. As a result, GTP-bound Rac can activate PAK (p21-activated kinase) to induce the assembly of F-actin filaments, and active GTP-bound Ras causes integrin-mediated adhesion to the extracellular matrix (ECM), leading to cell migration. The binding of Sema3E with plexinD1 leads to a conformational change in which the GAP domain and RBD bind to an active form of R-Ras and Rac GTPase, respectively. By sequestering Rac and Ras, plexinD1 inactivates PAK and hydrolyzes GTP to GDP. As a result, disassembly of actin filaments and inhibition of integrin binding to ECM lead to cell retraction. The binding of Sema3E with plexinD1 inhibits Ras-mediated other downstream signaling events .
| III-FUNCTIONS OF SEMA3E/PLEXIND1 AXIS|| |
Sema3E/plexinD1 axis plays a critical role in developing the nervous system, embryogenesis, vasculature and angiogenesis, tumor inhibition, cancer metastasis, thymocyte development, and allergic asthma.
Sema3E and its receptor plexinD1 are axon guidance molecules that play a vital role in developing the nervous system during embryogenesis. Sema3E and plexinD1 have been shown to play a role in the organization of neuronal circuits. Sema3E/plexinD1 acts as both chemorepellent and chemoattractant during nervous system development. For example, binding of the dimeric form of Sema3E with plexinD1 inhibits axon growth cone migration in the absence of neuropilin. However, in the presence of neuropilin, the binding of the monomeric form of Sema3E to plexinD1 acts as a chemoattractant leading to axon growth cone migration . Studies have shown that the repulsion activity of plexinD1 blocks the synapse formation that leads to sensory-motor connectivity . Again, Sema3E/plexinD1 plays an essential role in the development of the hippocampus during embryonic, perinatal, postnatal, and adult stages, whereas the absence of plexinD1/Sema3E leads to abnormal hippocampal formation .
Tumor and cancer
PlexinD1 can act as both pro- and anti-tumor based on the cancer type and location and interaction with a specific isoform of Sema3E. Full-length Sema3E (P87-Sema3E) has no prometastatic activity when small proteolytic fragments Sema3E (P61-Sema3E) are prometastatic. PlexinD1 expression is positively correlated with the progression of tumor metastatic . In human colon cancer, the level of plexinD1 and Sema3E increased in the metastasis cancer cells when compared with tumor cells, and Sema3E expression and signaling through plexinD1 positively correlate with metastatic progression . However, deletion of plexinD1 from tumor cells abrogates the metastatic effect of P61-Sema3E . Moreover, Sema3E induced intestinal gastric and pancreatic cancer cell growth. The enhanced expression level of Sema3E correlated with the metastasis of gastric cancer in the intestine and poor pancreatic patient survival [37,38]. Furthermore, Sema3E of ovarian tumor induces epithelial-to-mesenchymal transition and cell migration and malignant progression via plexinD1 . PlexinD1/Sema3E axis inhibits tumor apoptosis and causes breast cancer metastasis. Also, the inhibition of plexinD1 signaling induced apoptosis of breast cancer cells . In contrast, mutated furin-resistant Sema3E isoform, full length, inhibits tumor angiogenesis and metastatic spreading .
PlexinD1 plays a role in the direction of migration of thymocytes during T-cells maturation. Sema3E/plexinD1 axis regulates the thymocyte movement from cortex to medulla during T-cells development. The double-positive (DP) thymocytes (CD4+CD8+) express plexinD1, and its activation through Sema3E binding suppresses CCR9/CCL25 signaling. This suppression results in DP thymocytes moving from cortex to medulla, leading to the maturation of thymocytes into single positive (SP) T-cells. In the absence of plexinD1, DP thymocytes remain in the cortex and mature into single-positive thymocytes that form ectopic SP clusters in the cortex, resulting in disruption of the cortico-medullary junction in the thymus .
Vasculature and angiogenesis
Sema3E/plexinD1 axis plays a critical role in angiogenesis where it regulates the positioning of ECs and cardio-vasculature patterning [16,43]. Moreover, the absence of plexinD1 induced new blood vessels formation because Sema3E/plexinD1 signaling inhibits VEGF-induced angiogenesis by inducing the decoy receptor VEGFR1. As a result, VEGF is trapped by VEGFR-1 and cannot bind with VEGFR2 leading to VEGF-mediated endothelial growth inhibition . In ECs, Sema3E/plexinD1 signaling mediates actin filament disassembly and dysregulates integrin binding to the ECM. This effect results in the inhibition of EC migration and proliferation, leading to angiogenesis inhibition [43,45].
| IV-SEMA3E/PLEXIND1 IN ASTHMA|| |
Sema3E is the canonical receptor for plexinD1 and can directly bind to plexinD1 with high affinity . Different studies have shown that the PlexinD1/Sema3E axis regulates allergic asthma, and Sema3E deficiency exacerbates allergen-induced airway hyperresponsiveness, airway inflammation, and airway remodeling .
| PLEXIND1/SEMA3E AXIS IN HUMAN ASTHMA|| |
ASM mass is increased in patients with asthma due to a higher proliferation rate of human ASM cells (HASMCs) compared with healthy subjects . Both healthy and asthmatics HASMCs constitutively express plexinD1; however, expression was decreased in asthmatics compared with healthy subjects . Sema3E inhibits platelet-derived growth factor-mediated HASMC proliferation and migration . This study suggests that plexinD1/Sema3E downregulates airway remodeling by inhibiting ASM cell proliferation.
Moreover, Sema3E is mainly expressed by airway epithelial cells  and the expression of Sema3E robustly decreased in bronchial biopsy and bronchoalveolar lavage of patients with severe asthma. Furthermore, there is a strong correlation between Sema3E expression and forced expiratory volume in 1 s (FEV1) . These suggest that Sema3E might downregulate asthma by reducing the release of inflammatory mediators from epithelial cells, thus decreasing the recruitment of inflammatory effector cells to the airway. Further, considering the importance of Sema3E regulatory role in airway neutrophilia and Th17 pathway, recombinant Sema3E protein as an “add-on” drug for the steroid-resistant severe asthmatics may be considered in clinical practice.
Sema3E inhibits chemokine-induced neutrophils migration in vitro and in vivo. Human neutrophils constitutively express plexinD1. PlexinD1/Sema3E interaction on neutrophils suppresses CXCL8/IL-8-induced primary human neutrophils migration by repression of Rac1 GTPase activity and F-actin polymerization. In vivo, Sema3E/plexinD1 reduced lipopolysaccharide (LPS)-induced airway neutrophilia .
PlexinD1/Sema3E in asthma model
Sema3E deficiency exacerbates house dust mite (HDM)-induced acute and chronic asthma features, including airway inflammation, airway hyperresponsiveness, and remodeling. This was manifested by an increased number of CD11b+cDC, eosinophils, neutrophils, Th2 and Th17 cytokine responses, mucus overproduction, and collagen deposition [46,49]. However, recovery of Sema3E/plexinD1 axis by treating exogenous Sema3E-Fc recombinant protein reduced these asthma features . Sema3E deficiency-induced neutrophilia in the airway was increased upon HDM or LPS exposure, and treatment with recombinant Sema3E reduces allergen-induced neutrophils infiltration to the airway . More recently, Sema3E-deficient mice subjected to acute HDM challenge showed increased angiogenesis in the airway compared with their wild-type counterpart. However, treatment with Sema3E-Fc recombinant protein reduced pro-angiogenic factor VEGF and VEGFR2 and promoted anti-angiogenic factor VEGFR1 . In Sema3E knocked-out mice, the deposited collagen levels in the lamina reticularis and mucus production surged upon the HDM challenge. In response to Sema3E-Fc treatment, collagen deposition and associated fibrosis and mucus hyperproduction were decreased in a chronic allergic asthma model [49,50]. Another study demonstrated that Sema3E impacts ASMC contractile phenotype in hemostatic and asthmatic conditions . Intranasal administration of recombinant Sema3E-Fc significantly reduced the airway contraction and decreased the half-maximal effective concentration of methacholine [49, 50, 52]. Therefore, Sema3E is an essential molecule that regulates allergic responses and can have an anti-contractile effect on airways in the allergic asthma model.
Mechanistically, Sema3E plays an essential role in DC function in asthma. In the Sema3E-deficient mice, the number of CD11b+CD103 DCs was enhanced upon HDM challenge, which resulted in priming Th2/Th17 responses. Furthermore, IL-5, IL-13, IL-4, and IL-17A levels increased, leading to eosinophil accumulation, IgE class switching, and neutrophil recruitment, respectively [46,50]. Similarly, the adoptive transfer of CD11b+ DCs from Sema3E knocked-out mice to wild-type counterpart, the responses mentioned earlier is enhanced remarkably. This finding emphasized the importance of Sema3E in DC-associated eosinophilia and neutrophilia in the airways [28,50]. Genetic deletion of Sema3E in mice was associated with higher HDM uptake by respiratory CD11b+ IRF-4+ cDC, suggesting a critical regulatory role for Sema3E in pulmonary DC function during asthma .
More recently, we showed that Sema3E/PlexinD1 axis plays a key role in interstitial macrophage (IM) responses during asthma. PLXND1 ablation in CX3CL1+ IM led to higher HDM-specific IgE and Th2/Th17 cytokines, including IL-4, IL-13, and IL-17A, which can control the airway eosinophils and neutrophils accumulation . Moreover, PLXND1 deletion in bone marrow-derived macrophages decreased the IL-10 mRNA ex vivo  in line with the exacerbated inflammatory responses in Cx3cr1creERT2-Plxnd1 knocked-out mice.
| Conclusion|| |
Our current understanding of the impact of Sema3E/PlexinD1 on inflammation, remodeling, and AHR has painted a fascinating, incomplete picture of this axis, which could be a potential node for therapeutic intervention in asthma.
All authors equally contributed to this research. The authors have approved the final draft of the manuscript and take responsibility for its integrity and scientific contents.
Financial support and sponsorship
This study was funded by a project grant from the Canadian Institute of Health Research (Grant# PJT 173291) to ASG.
Conflicts of interest
There are no conflicts of interest.
Data availability statement
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[Figure 1], [Figure 2]