CD95-Ligand on Peripheral Myeloid Cells Activates Syk Kinase to Trigger Their Recruitment to the Inflammatory Site

Abstract

Injury to the central nervous system initiates an uncontrolled inflammatory response that results in both tissue repair and destruction. Here, we showed that, in rodents and humans, injury to the spinal cord triggered surface expression of CD95 ligand (CD95L, FasL) on peripheral blood myeloid cells. CD95L stimulation of CD95 on these cells activated phosphoinositide 3-kinase (PI3K) and metalloproteinase-9 (MMP-9) via recruitment and activation of Syk kinase, ultimately leading to increased migration. Exclusive CD95L deletion in myeloid cells greatly decreased the number of neutrophils and macrophages infiltrating the injured spinal cord or the inflamed peritoneum after thioglycollate injection. Importantly, deletion of myeloid CD95L, but not of CD95 on neural cells, led to functional recovery of spinal injured animals. Our results indicate that CD95L acts on peripheral myeloid cells to induce tissue damage. Thus, neutralization of CD95L should be considered as a means to create a controlled beneficial inflammatory response.

Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels

“…This is consistent with previous reports indicating that Syk is critical for integrin signaling to the cytoskeleton, 50 cell migration 51 and the recruitment toward inflammatory sites. 52 As DCs need to migrate toward secondary lymphoid organs and present antigen to effectively prime the allogeneic Tcs, interference with this step may block the pathogenesis of GvHD at an early stage. Beside its relevance for cell migration, the integrity of the actin cytoskeleton is essential for efficient formation of the immunological synapse, 53 which may be an additional mechanism of how Syk inhibition could impact DC --Tc interaction.…”

How CD95 stimulates invasion

“…13,18,21,22 CD95 is found in a complex with Src-family tyrosine kinases; 23 it stimulates tyrosine kinase activity, 23,24 and it is phosphorylated on tyrosine itself. 25,26 In addition to activating tyrosine kinases of the Src family, CD95 also activates the EGFR in hepatocytes and hepatic stellate cells, 27 the PDGF receptor in invasion-prone tumor cells 22 and Syk in ©2 0 1 1 L a n d e s B i o s c i e n c e .…”

“…56,57 myeloid cells. 21 How CD95 stimulation leads to tyrosine kinase activation is still largely unclear. Likewise, the exact sequence of tyrosine phosphorylation events downstream of CD95 remains to be established.…”

“…Activation of the PI3K pathway downstream of tyrosine kinase activity appears to be commonly observed following CD95L stimulation and to be essential for CD95-induced (tumor) cell invasion. 13,18,21 Interestingly, activation of PI3K appears to be especially important during the metastatic process. 34,35 The identity of the CD95-activated tyrosine kinase(s) and the specific tyrosine-phosphorylated docking proteins mediating p85 recruitment are likely to be cell type-specific.…”

“…CD95 promotes adhesion of macrophages to ICAM, 21 presumably involving the β2 integrin LFA-1. 64 Furthermore, CD95 increases binding of epithelial renal tubular cells to vitronectin by stimulating expression of β8-integrin, and this is required for CD95-stimulated cell migration.…”