title: Contribution of CD95 to the activation of innate  immune response
creator: Gao, Liang
subject: ddc-570
subject: 570 Life sciences
description: Myeloid cell recruitment plays a pivotal role in innate immune response. It comprises a cascade of sequential cellular processes including slow rolling, activation and firm adhesion, and transendothelial cell migration. Apart from the well-known apoptotic function, CD95 serves as an inflammatory mediator by inducing production of cytokines and chemokines in a variety of cell types and triggering myeloid cell transmigration to inflammatory sites via Syk-PI3K-MMP9 signaling pathway.  Utilizing an ex vivo autoperfused mouse flow chamber assay, we show here that CD95 ligand (CD95L) induces neutrophil slow rolling. Engagement of CD95 with CD95 ligand in myeloid cells activates the signaling pathway of Syk-BTK-PLC-γ2, which is essential for selectin-induced integrin activation in neutrophil slow rolling. Furthermore, activation of Rap1, which serves as a direct mediator for integrin activation, by CD95 signaling in neutrophils suggests the involvement of integrin activation in CD95-induced slow rolling. In line with this hypothesis, integrin activation upon CD95L treatment was detected by performing active integrin reporter antibodies binding assay and soluble ICAM1 binding assay. In addition to activating integrin, CD95 recruits integrin and forms microclusters upon CD95L stimulation. Our results indicate that CD95 signaling activates integrin in mediating neutrophils slow rolling.  We also found the involvement of endothelia cells and Ly6Chi monocytes - the classical inflammatory monocytes- in CD95-mediated innate response. Inducible deletion of CD95L in endothelial cells (CD95Lf/f;Ve-CadherinERT2/4cre) impaired neutrophil recruitment in a thioglycollate-induced peritonitis model. Unlike TNF-α, deletion of CD95 in endothelial cells (CD95f/f;Ve-CadherinERT2/4cre) had no impact on the expression levels of adhesion molecules and neutrophil recruitment. Moreover, CD95 selectively induced the mobilization and recruitment of inflammatory monocytes in a CCL2-dependent manner.  In this study we show for the first time that CD95 signaling mediates neutrophil slow rolling via activation of integrin. Endothelial cells participate in this process by presenting CD95L. CD95 is also involved in the recruitment of inflammatory monocytes. Taken together with our previous findings, our studies identify a CD95 chemotactic axis pathway for innate immune cell recruitment.
publisher: Heidelberg University Library
date: 2016
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/17890/1/Liang%20Gao%20A290%20PhD%20Thesis.pdf
identifier: DOI:10.11588/heidok.00017890
identifier: urn:nbn:de:bsz:16-heidok-178909
identifier:   Gao, Liang  (2016) Contribution of CD95 to the activation of innate immune response.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/17890/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng