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

Smith EP, Shanks K, Lipsky MM, DeTolla LJ, Keegan AD, Chapoval SP - BMC Immunol. (2011)

Bottom Line: Sema4A and Sema4D were the first semaphorins found to be expressed on immune cells and were termed "immune semaphorins".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.CD72 was found on lung immune, inflammatory, and epithelial cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

ABSTRACT

Background: Semaphorins 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.

Results: Allergen 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.

Conclusions: This 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.

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Lung exposure to either allergen or VEGF induces asthma-like inflammatory responses. (A-B) WT mice were exposed to OVA as described in the Methods section. Significant influx of eosinophils, lymphocytes, and neutrophils into BAL of allergen-treated WT mice was found compared to PBS-treated counterparts (*p < 0.025, 0.045, and 0.03, correspondingly) (A). Lung tissue inflammatory response observed on histology slides corresponds that in BAL (magnification x20, for insert 100x) (B). (C-D) Lung VEGF expression induces local inflammation and upregulation of selected neuroimmune semaphorin and receptor molecules in sorted lung conventional DC. H&E staining of lungs from WT and VEGF tg mice given DOX water for 7 days (magnification 40x) (C). Sorted mouse lung cDC were subjected to tRNA extraction followed by cDNA preparation and PCR with gene-specific primers. Note a strong upregulation of Sema4D and CD72 in lung cDC by VEGF (D).
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Figure 1: Lung exposure to either allergen or VEGF induces asthma-like inflammatory responses. (A-B) WT mice were exposed to OVA as described in the Methods section. Significant influx of eosinophils, lymphocytes, and neutrophils into BAL of allergen-treated WT mice was found compared to PBS-treated counterparts (*p < 0.025, 0.045, and 0.03, correspondingly) (A). Lung tissue inflammatory response observed on histology slides corresponds that in BAL (magnification x20, for insert 100x) (B). (C-D) Lung VEGF expression induces local inflammation and upregulation of selected neuroimmune semaphorin and receptor molecules in sorted lung conventional DC. H&E staining of lungs from WT and VEGF tg mice given DOX water for 7 days (magnification 40x) (C). Sorted mouse lung cDC were subjected to tRNA extraction followed by cDNA preparation and PCR with gene-specific primers. Note a strong upregulation of Sema4D and CD72 in lung cDC by VEGF (D).

Mentions: Allergen treatment of WT mice induced a significant influx of inflammatory cells into the lungs measured by cell counts in the BAL and the H&E staining of lung tissue (Figure 1 A and 1B). Eosinophils were found to dominate the cellular infiltrate in the BAL of OVA-treated mice mounting to 147,233 ± 61,999 cells whereas they were absent in the BAL of PBS-treated mice (0 ± 0). Lung tissue histochemistry pictures corresponded that of BAL cell composition (Figure 1 B).


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

Smith EP, Shanks K, Lipsky MM, DeTolla LJ, Keegan AD, Chapoval SP - BMC Immunol. (2011)

Lung exposure to either allergen or VEGF induces asthma-like inflammatory responses. (A-B) WT mice were exposed to OVA as described in the Methods section. Significant influx of eosinophils, lymphocytes, and neutrophils into BAL of allergen-treated WT mice was found compared to PBS-treated counterparts (*p < 0.025, 0.045, and 0.03, correspondingly) (A). Lung tissue inflammatory response observed on histology slides corresponds that in BAL (magnification x20, for insert 100x) (B). (C-D) Lung VEGF expression induces local inflammation and upregulation of selected neuroimmune semaphorin and receptor molecules in sorted lung conventional DC. H&E staining of lungs from WT and VEGF tg mice given DOX water for 7 days (magnification 40x) (C). Sorted mouse lung cDC were subjected to tRNA extraction followed by cDNA preparation and PCR with gene-specific primers. Note a strong upregulation of Sema4D and CD72 in lung cDC by VEGF (D).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3118960&req=5

Figure 1: Lung exposure to either allergen or VEGF induces asthma-like inflammatory responses. (A-B) WT mice were exposed to OVA as described in the Methods section. Significant influx of eosinophils, lymphocytes, and neutrophils into BAL of allergen-treated WT mice was found compared to PBS-treated counterparts (*p < 0.025, 0.045, and 0.03, correspondingly) (A). Lung tissue inflammatory response observed on histology slides corresponds that in BAL (magnification x20, for insert 100x) (B). (C-D) Lung VEGF expression induces local inflammation and upregulation of selected neuroimmune semaphorin and receptor molecules in sorted lung conventional DC. H&E staining of lungs from WT and VEGF tg mice given DOX water for 7 days (magnification 40x) (C). Sorted mouse lung cDC were subjected to tRNA extraction followed by cDNA preparation and PCR with gene-specific primers. Note a strong upregulation of Sema4D and CD72 in lung cDC by VEGF (D).
Mentions: Allergen treatment of WT mice induced a significant influx of inflammatory cells into the lungs measured by cell counts in the BAL and the H&E staining of lung tissue (Figure 1 A and 1B). Eosinophils were found to dominate the cellular infiltrate in the BAL of OVA-treated mice mounting to 147,233 ± 61,999 cells whereas they were absent in the BAL of PBS-treated mice (0 ± 0). Lung tissue histochemistry pictures corresponded that of BAL cell composition (Figure 1 B).

Bottom Line: Sema4A and Sema4D were the first semaphorins found to be expressed on immune cells and were termed "immune semaphorins".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.CD72 was found on lung immune, inflammatory, and epithelial cells.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

ABSTRACT

Background: Semaphorins 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.

Results: Allergen 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.

Conclusions: This 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.

Show MeSH
Related in: MedlinePlus