Neuroimmune semaphorin 4A downregulates the severity of allergic response

Nkyimbeng-Takwi, E.H.; Shanks, Kathleen; Smith, E. L.; Iyer, Apoorva; Mm, Lipsky; DeTolla, LJ; Kikutani, Hitoshi; Keegan, AD; Chapoval, Svetlana P

doi:10.1038/mi.2012.18

Cited by 42 publications

(66 citation statements)

References 52 publications

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“…Furthermore, bronchoalveolar lavage (BAL) fluid of Sema4A-deficient mice contains elevated levels of Th2 cytokines and IgE, as well as higher levels of pulmonary eosinophil infiltration. These data suggest that Sema4A is involved in the regulation of Th2-driven pathophysiology in the lung 25,26 . These results suggest that Sema4A plays a suppressive role in Th2-driven disease while driving Th1-driven diseases, such as EAE.…”

Section: Sema4a and Immune Responsesmentioning

confidence: 64%

The role of Sema4A in angiogenesis, immune responses, carcinogenesis, and retinal systems

Ito¹,

Kumanogoh²

2016

Cell Adhesion & Migration

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Semaphorins were originally identified as axon guidance cues that regulate the functional activity of axons in the nervous system. In addition, accumulating evidence indicates that semaphorins have multiple functions in physiological and pathogenic processes, including vascular development, tumor progression, and immune responses. Sema4A is a semaphorin expressed in immune cells, and is thus termed an “immune semaphorin.” Sema4A has 4 types of receptors: Plexin D family, Plexin B family, Tim-2, and Nrp-1. Recent studies suggest that Sema4A plays critical roles in many processes including cell–cell interactions, immune-cell activation, differentiation, and migration. In other studies, Sema4A is also associated with carcinogenesis and retinal systems. In this review, we summarize current knowledge regarding the biology of Sema4A in relation to angiogenesis, immune responses, colorectal cancer, and the retina.

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Section: Sema4a and Immune Responsesmentioning

confidence: 64%

The role of Sema4A in angiogenesis, immune responses, carcinogenesis, and retinal systems

Ito¹,

Kumanogoh²

2016

Cell Adhesion & Migration

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“…Bronchoalveolar lavages (BAL) were performed 48h after last Ag nebulization, cells and BALF collected, cytospin made and cell counts performed as described earlier [28, 33]. Five times (5×) concentrated (Amicon Ultra 3K membranes, Millipore) BAL fluid and intact serum sample’s cytokine and chemokine levels were determined using Searchlight Proteome Array (Aushon), ELISA kits (R&D Systems), and CBA kits (552364, BD Biosciences) [28, 33].…”

Section: Methodsmentioning

confidence: 99%

“…Five times (5×) concentrated (Amicon Ultra 3K membranes, Millipore) BAL fluid and intact serum sample’s cytokine and chemokine levels were determined using Searchlight Proteome Array (Aushon), ELISA kits (R&D Systems), and CBA kits (552364, BD Biosciences) [28, 33]. Array and CBA data were analyzed using the ArrayVision software and FlowJo plus BD CBA softwares, correspondingly.…”

Section: Methodsmentioning

confidence: 99%

“…One such novel pathway relates to the T cell costimulatory molecule Sema4A [21, 22] which, in addition to its previously defined T cell co-stimulatory function [21, 22], also has many other cellular and tissue effects such as neuron axonal guidance [23, 24], photoreceptor survival [25, 26], and angiogenesis [27]. We previously have shown that Sema4A −/− mice display a significantly higher acute allergic inflammatory response as compared to WT mice [28]. Therefore, in contrast to its stimulatory role in Th1-mediated diseases, Sema4A plays a downregulatory role in allergic asthma severity.…”

Section: Introductionmentioning

confidence: 99%

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Neuroimmune semaphorin 4A as a drug and drug target for asthma

Mogie¹,

Shanks²,

Nkyimbeng-Takwi³

et al. 2013

International Immunopharmacology

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Neuroimmune semaphorin 4A (Sema4A) has been shown to play an important costimulatory role in T cell activation and regulation of Th1-mediated diseases such as multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), and experimental autoimmune myocarditis (EAM). Sema4A has three functional receptors, Tim-2 expressed on CD4+ T cells, Th2 cells in particular, and Plexin B1 and D1 predominantly expressed on epithelial and endothelial cells, correspondingly. We recently showed that Sema4A has a complex expression pattern in lung tissue in a mouse model of asthma. We and others have shown that corresponding Plexin expression can be found on immune cells as well. Moreover, we demonstrated that Sema4A-deficient mice displayed significantly higher lung local and systemic allergic responses pointing to its critical regulatory role in the disease. To determine the utility of Sema4A as a novel immunotherapeutic, we introduced recombinant Sema4A protein to the allergen-sensitized WT and Sema4A−/− mice before allergen challenge. We observed significant reductions in the allergic inflammatory lung response in Sema4A-treated mice as judged by tissue inflammation including eosinophilia and mucus production. Furthermore, we demonstrated that in vivo administration of anti-Tim2 Ab led to a substantial upregulation of allergic inflammation in WT mouse lungs. These data highlight the potential to develop Sema4A as a new therapeutic for allergic airway disease.

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“…Sema4A is an important regulator of Th2-driven lung pathophysiology, where it markedly reduces the severity of allergic airway inflammation. Genetic deletion of Sema4A resulted in an inflammatory response that was associated with a selective increase in bronchoalveolar lavage IL-13 content, augmented airway hyper-reactivity, and lower regulatory T cell (Treg) numbers following ovalbumin-induced inflammation [29]. Sema4A also activates mTOR signaling through Plexin B2 and helps to induce the differentiation of CD8+ cells.…”

Section: Trendsmentioning

confidence: 99%