An Inhibitory Role for Sema4A in Antigen-Specific Allergic Asthma

Morihana, Tetsuo; Goya, Sho; Mizui, Masayuki; Yasui, Takeshi; Prasad, Durubaka V. R.; Kumanogoh, Atsushi; Tamura, Manabu; Shikina, Takashi; Maeda, Yohei; Iwamoto, Yasuhiro; Inohara, Hidenori; Kikutani, Hitoshi

doi:10.1007/s10875-012-9798-5

Cited by 28 publications

(27 citation statements)

References 39 publications

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“…Sema4A is a key molecule in the regulation of T cell homeostasis, activation, and Th1/2/17 differentiation . Sema4A deficiency or inhibition reduces disease severity in murine models of multiple sclerosis (MS) and autoimmune myocarditis, but enhances the severity of experimental asthma due to impaired Th1/Th17 differentiation and skewing towards a Th2 polarization . Reciprocally, serum levels of Sema4A are increased in MS patients and positively associated with Th17 skewing .…”

Section: Introductionmentioning

confidence: 99%

Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis

Carvalheiro

Affandi

Malvar‐Fernández

et al. 2019

Arthritis & Rheumatology

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Objective To analyze the potential role of semaphorin 4A (Sema4A) in inflammatory and fibrotic processes involved in the pathology of systemic sclerosis (SSc). Methods Sema4A levels in the plasma of healthy controls (n = 11) and SSc patients (n = 20) were determined by enzyme‐linked immunosorbent assay (ELISA). The expression of Sema4A and its receptors in monocytes and CD4+ T cells from healthy controls and SSc patients (n = 6–7 per group) was determined by ELISA and flow cytometry. Th17 cytokine production by CD4+ T cells (n = 5–7) was analyzed by ELISA and flow cytometry. The production of inflammatory mediators and extracellular matrix (ECM) components by dermal fibroblast cells (n = 6) was analyzed by quantitative polymerase chain reaction, ELISA, Western blotting, confocal microscopy, and ECM deposition assay. Results Plasma levels of Sema4A, and Sema4A expression by circulating monocytes and CD4+ T cells, were significantly higher in SSc patients than in healthy controls (P < 0.05). Inflammatory mediators significantly up‐regulated the secretion of Sema4A by monocytes and CD4+ T cells from SSc patients (P < 0.05 versus unstimulated SSc cells). Functional assays showed that Sema4A significantly enhanced the expression of Th17 cytokines induced by CD3/CD28 in total CD4+ T cells as well in different CD4+ T cell subsets (P < 0.05 versus unstimulated SSc cells). Finally, Sema4A induced a profibrotic phenotype in dermal fibroblasts from both healthy controls and SSc patients, which was abrogated by blocking or silencing the expression of Sema4A receptors. Conclusion Our findings indicate that Sema4A plays direct and dual roles in promoting inflammation and fibrosis, 2 main features of SSc, suggesting that Sema4A might be a novel therapeutic target in SSc.

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Section: Introductionmentioning

confidence: 99%

Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis

Carvalheiro

Affandi

Malvar‐Fernández

et al. 2019

Arthritis & Rheumatology

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“…Indeed, Sema4adeficient mice exhibit a phenotype of severe allergic dermatitis that resembles AD (Morihana et al 2013). As already described, Sema4A is crucial for helper T-cell differentiation and polarization, and Sema4A deficiency causes disruption of Th1/Th2 balance .…”

Section: Allergic Dermatitismentioning

confidence: 76%

“…Decreased Sema3A expression has been observed in the nasal mucosa during allergic rhinitis (Sawaki et al 2011). Further analysis of these mice revealed increased pulmonary eosinophil infiltration and increased levels of Th2 cytokines and IgE in bronchoalveolar lavage (BAL) fluid (Morihana et al 2013;Nkyimbeng-Takwi et al 2012). In a study that used a model of ovalbumin (OVA)-specific experimental asthma, Sema4a-deficient mice exhibited enhanced airway hyperreactivity.…”

Section: Allergic Rhinitis and Asthmamentioning

confidence: 99%

Semaphorins

2015

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“…In sum, our knowledge of transmembrane semaphorin functions and signaling pathways is still far from complete and further studies will be required to understand their relevance in development and cancer. Inhibitory role in allergic asthma 100 Required for optimal activation and differentiation of CD8+ T cells 101 Involved in rheumatoid arthritis 102…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Transmembrane semaphorins: Multimodal signaling cues in development and cancer

Gurrapu

Tamagnone

2016

Cell Adhesion & Migration

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Semaphorins constitute a large family of membrane-bound and secreted proteins that provide guidance cues for axon pathfinding and cell migration. Although initially discovered as repelling cues for axons in nervous system, they have been found to regulate cell adhesion and motility, angiogenesis, immune function and tumor progression. Notably, semaphorins are bifunctional cues and for instance can mediate both repulsive and attractive functions in different contexts. While many studies focused so far on the function of secreted family members, class 1 semaphorins in invertebrates and class 4, 5 and 6 in vertebrate species comprise around 14 transmembrane semaphorin molecules with emerging functional relevance. These can signal in juxtacrine, paracrine and autocrine fashion, hence mediating long and short range repulsive and attractive guidance cues which have a profound impact on cellular morphology and functions. Importantly, transmembrane semaphorins are capable of bidirectional signaling, acting both in "forward" mode via plexins (sometimes in association with receptor tyrosine kinases), and in "reverse" manner through their cytoplasmic domains. In this review, we will survey known molecular mechanisms underlying the functions of transmembrane semaphorins in development and cancer.

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An Inhibitory Role for Sema4A in Antigen-Specific Allergic Asthma

Abstract: These results demonstrate that Sema4A plays an inhibitory role in Th2-type allergic diseases, such as allergic asthma.

Cited by 28 publications

References 39 publications

Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis

Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis

Semaphorins

Transmembrane semaphorins: Multimodal signaling cues in development and cancer

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