Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury

 Andrés Hidalgo et al Nature Medicine 15, 384 - 391 (2009)

Speaker: Tsung-Ying Hsieh (謝宗穎)                             Time: 14:00~15:00, Nov. 11, 2009

Commentator: Dr. Bei-Chang Yang (楊倍昌老師)               Place: Room 601

Abstract:

Under inflammation, leukocyte recruitment is initiated by selectin-dependent tethering and rolling, followed by chemokine-mediated activation, integrin-dependent firm adhesion and, finally, extravasation into the underlying tissue. In activation step, the chemokine signal from endothelium can activate leukocytes via G protein-coupled receptors to activate integrins for the following steps. Recent studies have shown that in the initial step, the E-selectin on endothelium interacting with its ligand (PSGL-1, CD44) on leukocyte also can activate a_Lb₂ integrin and help the leukocytepolarization. Previous studies have reported that E-selectin can mediate activation of a_Mb₂ integrin. However, E-selectin ligand involved in this process is still unknown. In this study, the author utilized high-speed multichannel fluorescence intravital microscopy (MFIF) to analyze the interaction of leukocytes with RBCs and platelets. The results showed that heterotypic interactions of RBCs/platlets with leukocyte microdomains are induced during inflammation. The interaction was dependent on E-selectin. Next, author confirmed that E-selectin and E-selectin-ligand-1 (ESL-1) engagement could generate the activation signal for a_Mb₂ integrin. In other words, the activation of a_Mb₂ integrin on leukocyte leading edge can induce heterotypic interaction with platelets and RBCs. In two mouse model of thromboinjury diseases, transfusion-related acute lung injury (TRALI) and sickle cell disease (SCD), it was shown that E-selectin and ESL-1 interaction mediated the activation of a_Mb₂ on neutrophils for capturing platelets and sickle RBCs.  Inactivation of E-selectin or a_Mb₂ prevents tissue injury in both inflammatory models, suggesting that the heterotypic interaction indeed promotes organ damage and vaso-occlusion. The authors suggested the heterotypic interaction is mediated by polarized activation of a_Mb₂ induced by E-selectin - ESL-1 signal in neutrophils in these two thromboinflammatory injury models.

References：

1.  Andrés Hidalgo, Anna J. Peired, Martin K. Wild, Dietmar Vestweber, and Paul S. Frenette, Immunity. 26: 477-489 (2007).

2.  Alexander Zarbock, Clifford A. Lowell, and Klaus Ley. Immunity 26: 773-783, (2007).