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ICAM-1–activated Src and eNOS signaling increase endothelial cell surface PECAM-1 adhesivity and neutrophil transmigration
| Content Provider | Scilit |
|---|---|
| Author | Liu, Guoquan Place, Aaron T. Chen, Zhenlong Brovkovych, Viktor M. Vogel, Stephen M. Muller, William A. Skidgel, Randal A. Malik, Asrar B. Minshall, Richard D. |
| Copyright Year | 2012 |
| Description | Polymorphonuclear neutrophil (PMN) extravasation requires selectin-mediated tethering, intercellular adhesion molecule-1 (ICAM-1)–dependent firm adhesion, and platelet/endothelial cell adhesion molecule 1 (PECAM-1)–mediated transendothelial migration. An important unanswered question is whether ICAM-1–activated signaling contributes to PMN transmigration mediated by PECAM-1. We tested this concept and the roles of endothelial nitric oxide synthase (eNOS) and Src activated by PMN ligation of ICAM-1 in mediating PECAM-1–dependent PMN transmigration. We observed that lung PMN infiltration in vivo induced in carrageenan-injected WT mice was significantly reduced in $ICAM-1^{−/−}$ and $eNOS^{−/−}$ mice. Crosslinking WT mouse ICAM-1 expressed in human endothelial cells (ECs), but not the phospho-defective $Tyr^{518}$Phe ICAM-1 mutant, induced SHP-2–dependent Src $Tyr^{530}$ dephosphorylation that resulted in Src activation. ICAM-1 activation also stimulated phosphorylation of Akt $(p-Ser^{473}$) and eNOS $(p-Ser^{1177}$), thereby increasing NO production. PMN migration across EC monolayers was abolished in cells expressing the $Tyr^{518}$Phe ICAM-1 mutant or by pretreatment with either the Src inhibitor PP2 or eNOS inhibitor L-NAME. Importantly, phospho–ICAM-1 induction of Src signaling induced PECAM-1 $Tyr^{686}$ phosphorylation and increased EC surface anti–PECAM-1 mAb-binding activity. These results collectively show that ICAM-1–activated Src and eNOS signaling sequentially induce PECAM-1–mediated PMN transendothelial migration. Both Src and eNOS inhibition may be important therapeutic targets to prevent or limit vascular inflammation. |
| Related Links | https://ashpublications.org/blood/article-pdf/120/9/1942/1362775/zh803512001942.pdf |
| Ending Page | 1952 |
| Page Count | 11 |
| Starting Page | 1942 |
| DOI | 10.1182/blood-2011-12-397430 |
| Journal | Blood |
| Issue Number | 9 |
| Volume Number | 120 |
| Language | English |
| Publisher | American Society of Hematology |
| Publisher Date | 2012-08-30 |
| Access Restriction | Open |
| Subject Keyword | Research and Experimental Medicine Pecam Phosphorylation Pmn Src Icam Adhesion Enos Signaling Endothelial Cells Journal: Blood (Vol- 110, Issue- 9) |
| Content Type | Text |
| Resource Type | Article |
