Intranasal Administration of Semaphorin-3A Alleviates Sneezing and Nasal Rubbing in a Murine Model of Allergic Rhinitis

Sawaki, Haruna; Nakamura, Fumio; Aihara, Michiko; Nagashima, Yoji; Komori-Yamaguchi, Junko; Yamashita, Naoya; Nakazawa, Makoto; Goshima, Yoshio; Ikezawa, Zenrō

doi:10.1254/jphs.11005fp

Cited by 33 publications

(26 citation statements)

References 53 publications

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“…Since allergic rhinitis results from a hyperinnervation of sensory neurons in the nasal turbinate, and because SEMA3A is known to restrict the innervation of sensory neurons, a reduced SEMA3A expression in affected patients was assumed. Accordingly, reduced expression of Sema3a was found in the nasal epithelium of an allergic rhinitis murine model, in which the phenotype could be rescued by intranasal administration of recombinant Sema3a [Sawaki et al, 2011]. Nevertheless, the here reported patient with constitutionally reduced SEMA3A expression so far showed no signs of allergic rhinitis.…”

Section: Discussionmentioning

confidence: 64%

Biallelic SEMA3A defects cause a novel type of syndromic short stature

Hofmann

Zweier

Sticht

et al. 2013

American J of Med Genetics Pt A

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Chromosomal microarray testing is commonly used to identify disease causing de novo copy number variants in patients with developmental delay and multiple congenital anomalies. In such a patient we now observed an 150 kb deletion on chromosome 7q21.11 affecting the first exon of the axon guidance molecule gene SEMA3A (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A). This deletion was inherited from the healthy father, but considering the function of SEMA3A and phenotypic similarity to the knock‐out mice, we still assumed a pathogenic relevance and tested for a recessive second defect. Sequencing of SEMA3A in the patient indeed revealed the de novo in‐frame mutation p.Phe316_Lys317delinsThrSerSerAsnGlu. Cloning of the mutated allele in combination with two informative SNPs confirmed compound heterozygosity in the patient. While the altered protein structure was predicted to be benign, aberrant splicing resulting in a premature stop codon was proven by RT‐PCR to occur in about half of the transcripts from this allele. Expression profiling in human fetal and adult cDNA panels, confirmed a high expression of SEMA3A in all brain regions as well as in adult and fetal heart and fetal skeletal muscle. Normal intellectual development in the patient was surprising but may be explained by the remaining 20% of SEMA3A expression level demonstrated by quantitative RT‐PCR. We therefore report a novel autosomal recessive syndrome characterized by postnatal short stature with relative macrocephaly, camptodactyly, septal heart defect and several minor anomalies caused by biallelic mutations in SEMA3A. © 2013 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 64%

Biallelic SEMA3A defects cause a novel type of syndromic short stature

Hofmann

Zweier

Sticht

et al. 2013

American J of Med Genetics Pt A

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“…Furthermore, when recombinant sema3A was administered intra-nasally to these mice, sneezing and nasal rubbing symptoms were alleviated. This was an additional study showing evidence that sema3A may provide a novel therapy for AR and other atopic disorders such as conjunctivitis and bronchial asthma (21,22). Semaphorins are well reported to be regulators of airway smooth muscle (ASM) hyperplasia.…”

Section: Semaphorin3a In Atopic Diseasesmentioning

confidence: 99%

“…This inhibitory effect was associated with decreased tyrosine phosphorylation of PDGFR, down-regulation of Raci activation, STAT3 and GSK-3B phosphorylation. These findings suggest a functional contribution of sema3A-NP-1 axis in airway remodeling and that sema3A could become a useful therapy in treating hyper-reactive airway disorders (21,22). …”

mentioning

confidence: 93%

Semaphorin3A: A potential therapeutic tool in immune-mediated diseases

Vadasz

Toubi

2018

Eur J Rheumatol

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The significance of semaphorin3A (sema3A) in regulating immune-mediated inflammation is widely reported. There are multiple mechanisms involved in the process of sema3A-mediated regulation. One of them is the ability of sema3A to maintain a sufficient regulation of both T-cell and B-cell activation. Because it is involved in the pathogenesis of many autoimmune, infectious, and malignant diseases, sema3A turns to be a promising therapeutic tool to be studied and applied in these diseases. Keywords: Semaphorin 3A, immune mediated diseases, atopic diseases the other, it increased the serum level of the anti-inflammatory cytokine IL-10 (11). In line with these findings, sema3A expression was found to be decreased on CD4 + T cells of RA patients, whereas NP-1 expression on these cells was increased. CD4+NP-1+T cells, known as T regulatory cells and a source of IL-10, were reported to be decreased in RA. In this case, the addition of sema3A into a co-culture with T cells acts directly on CD4+NP-1+T cells and increases IL-10 production, supporting its therapeutic beneficial effect in RA (11). In a recent study, the expression of sema3A in synovial tissues of RA patients was investigated. Disease activity and the histological features of synovial tissues were also assessed in relation to sema3A expression. Human synovial tissues were obtained from established RA patients, compared those of patients suffering from osteoarthritis (OA), and assessed for sema3A, VEGF-A, and NP-1mRNA expression, using quantitative real-time polymerase chain reaction (qPCR). The protein expression of sema3A in synovial lining cells was decreased in RA tissues compared with that in OA samples. Sema3A mRNA levels correlated with the inflammation score, namely with the extent of lymphocyte infiltration (R=0.50, p=0.004). Thus, the correlation of sema3A expression in RA synovial tissues may become a therapeutic target in RA (12).Semaphorin3A and systemic lupus erythematosus (SLE): Hypothesizing that sema3A may have a similar role in SLE, we assessed its serum levels in SLE patients. Sema3A serum levels in SLE patients were found to be significantly lower than in RA patients (55.04±16.30 ng/mL vs. 65.54±14.82 ng/mL, p=0.018) and lower yet than in normal individuals (55.04±16.30 ng/ mL vs. 74.41±17.60 ng/mL, p<0.0001). Serum sema3A levels in SLE patients were low in negative correlation with SLE disease activity, renal damage, and the presence of relevant autoantibodies (R= −0.89, p<0.0001) (13). Being the source of autoantibodies and pro-inflammatory cytokines, the regulatory status of B cells was evaluated. The expression of sema3A on B regulatory (Breg) cells, namely CD19 + CD25high and NP-1 + was analyzed. As expected sema3A expression on these cells was significantly lower in SLE patients when compared to B cells from normal individuals, suggesting this to be in part responsible for B-cell auto-reactivity in SLE. Our other finding was the down-regulation of NP-1 expression on B cells from SLE patients, suggesting that both sema3A and N...

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“…Recently, it has been shown that hyperinnervation of sensory neurons in the nasal turbinate might be associated with the itching and sneezing. Since AR goes along with neural hypersensitivity, Sawaki et al [27] immunohistochemically examined the distribution of nerve fibers in the nasal mucosa and found that nerve-fiber density in the lamina propria was significantly increased in AR mice compared to control mice, which may correlate with the increased allergic symptoms. Since sema3A restricts innervation of sensory neurons by inhibiting the sprouting of nerve fibers, the researchers examined its contribution to the neural hypersensitivity in the nasal mucosa.…”

Section: Sema3a and Allergic Rhinitismentioning

confidence: 99%

“…1a). These results suggest that sema3A alleviates allergic symptoms such as sneezing and nasal rubbing behavior by suppressing hyperinnervations [27]. …”

Section: Sema3a and Allergic Rhinitismentioning

confidence: 99%

The Role of B Regulatory Cells and Semaphorin3A in Atopic Diseases

Vadasz

Haj²,

Toubi³

2014

Int Arch Allergy Immunol

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When the pathogenesis of allergic inflammatory diseases such as asthma, allergic rhinitis and atopic dermatitis is discussed, one should take into consideration the involvement of regulatory cells/molecules whose role is to prevent the induction and/or deterioration of such diseases. The involvement of T regulatory cells and FoxPp3 is well established in asthma, but only little is known about the involvement of B regulatory cells (Bregs) and the soluble regulatory molecule semaphorin3A (sema3A) in atopic diseases. During the last decade, research has sought to better define the various subtypes of Breg cells and how similar they are to their parallel subtypes of Tregs. In this review, we focus on the newly reported role of Bregs in both experimental and human models of asthma. Bregs are also involved in the pathophysiology of food allergy. We also show how sema3A plays a role in the pathogenesis of allergic rhinitis and atopic dermatitis. Determining the above processes could facilitate the use of regulatory molecules as therapeutic tools in treating these diseases.

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Intranasal Administration of Semaphorin-3A Alleviates Sneezing and Nasal Rubbing in a Murine Model of Allergic Rhinitis

Cited by 33 publications

References 53 publications

Biallelic SEMA3A defects cause a novel type of syndromic short stature

Biallelic SEMA3A defects cause a novel type of syndromic short stature

Semaphorin3A: A potential therapeutic tool in immune-mediated diseases

The Role of B Regulatory Cells and Semaphorin3A in Atopic Diseases

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