Deficiency of endothelial heparan sulfates attenuates allergic airway inflammation.
The effect of targeted inactivation of the gene encoding N-deacetylase/N-sulfotransferase-1 (Ndst1), a key enzyme involved in the biosynthesis of heparan sulfate (HS) chains, on the inflammatory response associated with allergic inflammation in a murine model of OVA-induced acute airway inflammation was investigated. OVA-exposed Ndst1(f/f)TekCre(+) (mutant) mice deficient in endothelial and leukocyte Ndst1 demonstrated significantly decreased allergen-induced airway hyperresponsiveness and inflammation characterized by a significant reduction in airway recruitment of inflammatory cells (eosinophils, macrophages, neutrophils, and lymphocytes), diminished IL-5, IL-2, TGF-beta1, and eotaxin levels, as well as decreased expression of TGF-beta1 and the angiogenic protein FIZZ1 (found in inflammatory zone 1) in lung tissue compared with OVA-exposed Ndst1(f/f)TekCre(-) wild-type littermates. Furthermore, murine eosinophils demonstrated significantly decreased rolling on lung endothelial cells (ECs) from mutant mice compared with wild-type ECs under conditions of flow in vitro. Treatment of wild-type ECs, but not eosinophils, with anti-HS Abs significantly inhibited eosinophil rolling, mimicking that observed with Ndst1-deficient ECs. In vivo, trafficking of circulating leukocytes in lung microvessels of allergen-challenged Ndst1-deficient mice was significantly lower than that observed in corresponding WT littermates. Endothelial-expressed HS plays an important role in allergic airway inflammation through the regulation of recruitment of inflammatory cells to the airways by mediating interaction of leukocytes with the vascular endothelium. Furthermore, HS may also participate by sequestering and modulating the activity of allergic asthma-relevant mediators such as IL-5, IL-2, and TGF-beta1.
Zuberi
Riaz I
RI
Department of Veterinary and Biomedical Sciences, University of Minnesota, St Paul, MN 55108, USA.
Ge
Xiao Na
XN
Jiang
Shuxia
S
Bahaie
Nooshin S
NS
Kang
Bit Na
BN
Hosseinkhani
Reza M
RM
Frenzel
Elizabeth M
EM
Fuster
Mark M
MM
Esko
Jeffrey D
JD
Rao
Savita P
SP
Sriramarao
P
P
D000818:Animals; D002633:Chemotaxis; D042783:Endothelial Cells / Q000201:enzymology*; D006497:Heparan Sulfate / Q000172:deficiency*; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D007376:Interleukin-2 / Q000032:analysis; D015848:Interleukin-5 / Q000032:analysis; D007962:Leukocytes / Q000201:enzymology*; D051379:Mice; D012130:Respiratory Hypersensitivity / Q000209:etiology / Q000473:pathology*; D015238:Sulfotransferases / Q000172:deficiency*; D053773:Transforming Growth Factor beta1 / Q000032:analysis
D006497:Heparan Sulfate; D007376:Interleukin-2; D015848:Interleukin-5; D015238:Sulfotransferases; D053773:Transforming Growth Factor beta1; C021350:heparitin sulfotransferase