title: Expression of neuroimmune semaphorins 4A and 4D and their receptors in the lung is enhanced by allergen and vascular endothelial growth factor.
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.
authors: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors: Elizabeth P
authors: EP
authors: Smith
authors: Kathleen
authors: K
authors: Shanks
authors: Michael M
authors: MM
authors: Lipsky
authors: Louis J
authors: LJ
authors: DeTolla
authors: Achsah D
authors: AD
authors: Keegan
authors: Svetlana P
authors: SP
authors: Chapoval
references: J Exp Med. 2005 Aug 1;202(3):437-44
references: 16043519
references: J Clin Invest. 1999 Jun;103(12):1707-17
references: 10377177
references: J Immunol. 2004 Apr 1;172(7):4545-55
references: 15034072
references: Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9017-22
references: 16754882
references: J Immunol. 2007 Nov 15;179(10):7030-41
references: 17982094
references: Blood. 2001 Jun 1;97(11):3498-504
references: 11369643
references: BMC Dev Biol. 2007 May 22;7:55
references: 17519029
references: J Immunol. 1998 May 1;160(9):4606-14
references: 9574568
references: J Immunol. 1998 Apr 15;160(8):4090-7
references: 9558120
references: J Exp Med. 2005 Mar 21;201(6):981-91
references: 15781587
references: J Immunol. 2009 Apr 15;182(8):4686-95
references: 19342644
references: J Immunol. 2006 Aug 15;177(4):2536-42
references: 16888015
references: Int J Mol Med. 2010 Feb;25(2):225-30
references: 20043131
references: Int Immunol. 2005 Apr;17(4):439-47
references: 15746246
references: Immunology. 2000 Dec;101(4):521-30
references: 11122456
references: Nat Med. 2004 Oct;10(10):1095-103
references: 15378055
references: BMC Cancer. 2009 Aug 25;9:297
references: 19703316
references: Immunity. 2000 Nov;13(5):621-31
references: 11114375
references: J Immunol. 2002 Aug 1;169(3):1175-81
references: 12133937
references: J Exp Med. 2001 Oct 15;194(8):1171-8
references: 11602645
references: Am J Physiol Lung Cell Mol Physiol. 2005 Aug;289(2):L274-9
references: 15833765
references: Cell Mol Life Sci. 2004 Feb;61(3):292-300
references: 14770294
references: Cell Mol Life Sci. 1998 Nov;54(11):1265-76
references: 9849618
references: J Immunol. 2000 Aug 15;165(4):2222-31
references: 10925310
references: Cell. 1999 Oct 1;99(1):71-80
references: 10520995
references: J Cell Sci. 2003 Sep 1;116(Pt 17):3463-70
references: 12893810
references: Immunity. 2005 Mar;22(3):305-16
references: 15780988
references: J Immunol. 2007 Sep 15;179(6):3488-94
references: 17785782
references: Nature. 2002 Oct 10;419(6907):629-33
references: 12374982
references: Clin Immunol. 2009 Sep;132(3):371-84
references: 19553159
references: Blood. 2009 Nov 12;114(20):4411-21
references: 19767511
references: EMBO J. 2007 Mar 7;26(5):1373-84
references: 17318185
references: Nat Immunol. 2008 Jan;9(1):17-23
references: 18087252
references: Am J Pathol. 2006 Feb;168(2):453-65
references: 16436660
references: Immunity. 2006 May;24(5):591-600
references: 16713976