Expression of neuroimmune semaphorins 4A and 4D and their receptors in the lung is enhanced by allergen and vascular endothelial growth factor

Abstract

BackgroundSemaphorins were originally identified as molecules regulating a functional activity of axons in the nervous system. Sema4A and Sema4D were the first semaphorins found to be expressed on immune cells and were termed "immune semaphorins". It is known that Sema4A and Sema4D bind Tim-2 and CD72 expressed on leukocytes and PlexinD1 and B1 present on non-immune cells. These neuroimmune semaphorins and their receptors have been shown to play critical roles in many physiological and pathological processes including neuronal development, immune response regulation, cancer, autoimmune, cardiovascular, renal, and infectious diseases. However, the expression and regulation of Sema4A, Sema4D, and their receptors in normal and allergic lungs is undefined.ResultsAllergen treatment and lung-specific vascular endothelial growth factor (VEGF) expression induced asthma-like pathologies in the murine lungs. These experimental models of allergic airway inflammation were used for the expression analysis of immune semaphorins and their receptors employing immunohistochemistry and flow cytometry techniques. We found that besides accessory-like cells, Sema4A was also detected on bronchial epithelial and smooth muscle cells, whereas Sema4D expression was high on immune cells such as T and B lymphocytes. Surprisingly, under inflammation various cell types including macrophages, lymphocytes, and granulocytes in the lung expressed Tim-2, a previously defined marker for Th2 cells. CD72 was found on lung immune, inflammatory, and epithelial cells. Bronchial epithelial cells were positive for both plexins, whereas some endothelial cells selectively expressed Plexin D1. Plexin B1 expression was also detected on lung DC. Both allergen and VEGF upregulated the expression of neuroimmune semaphorins and their receptors in the lung tissue. However, the lung tissue Sema4A-Tim2 expression was rather weak, whereas Sema4D-CD72 ligand-receptor pair was vastly upregulated by allergen. Soluble Sema4D protein was present in the lung lysates and a whole Sema4A protein plus its dimer were readily detected in the bronchoalveolar (BAL) fluids under inflammation.ConclusionsThis study clearly shows that neuroimmune semaphorins Sema4A and Sema4D and their receptors might serve as potential markers for the allergic airway inflammatory diseases. Our current findings pave the way for further investigations of the role of immune semaphorins in inflammation and their use as potential therapeutic targets for the inflammatory lung conditions.

Semaphorin 4A Exerts a Proangiogenic Effect by Enhancing Vascular Endothelial Growth Factor-A Expression in Macrophages

“…3D, 3E). (2,24). Therefore, we evaluated the expression of Tim-2 in peritoneal cells upon thioglycollate treatment.…”

“…Sema4A-deficient mice displayed defective Th1 responses, indicating that the induction of Sema4A in Th1 cells is necessary for their differentiation either by cognate cellular interactions among Th1 cells or by following an autocrine pathway (23). Recently, Sema4A has been shown to be upregulated by allergen or VEGF in bronchial epithelial cells expressing both PlexinD1 and PlexinB1, thus pointing to Sema4A as a potential player for the allergic airway inflammatory diseases (24).…”

Semaphorin 4D is expressed constitutively by human eosinophils

“…We used the several cytokines (IL-3, IL-5, GM-CSF, TNF-a, b-NGF, and VEGF) which were reported the activated effect for eosinophils or the enhanced expression for semaphorin receptors for priming. 10,11 There is a possibility that up-regulation of semaphorin receptors and direct effect of semaphorin are led in eosinophils by other priming methods. Previous study reported that sema7A expressed on eosinophils and sema7A protein on the surface of blood eosinophils was increased more by IL-3 than by GM-CSF or IL-5.…”

Análise da atividade de CD100 na modulação da ativação de macrófagos e sua infectividade por Leishmania (Leishmania) amazonensis.

“…Diversos trabalhos estudaram os efeitos de CD100 associado a receptores específicos para essa molécula. Uma análise da expressão de proteínas conhecidas como receptores potenciais de CD100 mostrou que, em camundongos, CD72 é um importante receptor de CD100 expresso em células epiteliais brônquicas, macrófagos alveolares, células B, DCs, fibroblastos e basófilos (MIZUI et al, 2009, SMITH et al, 2011. CD72 contêm motivos denominados tyrosine inibitory motifs (ITIMs) em sua região citoplasmática, e a proteína tyrosine phosphatase 1 (SHP-1) que está associada aos ITIMs regula negativamente a resposta imune (KUMANOGOH e KIKUTANI,…”