CD95-ligand on peripheral myeloid cells activates Syk kinase to trigger their recruitment to the inflammatory site.
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.
Molecular Neurobiology Unit, German Cancer Research Center, Heidelberg 69120, Germany.
Elisabeth
E
Letellier
Sachin
S
Kumar
Ignacio
I
Sancho-Martinez
Stefanie
S
Krauth
Anne
A
Funke-Kaiser
Sabrina
S
Laudenklos
Katrin
K
Konecki
Stefan
S
Klussmann
Nina S
NS
Corsini
Susanne
S
Kleber
Natalia
N
Drost
Andreas
A
Neumann
Matthieu
M
Lévi-Strauss
Benedikt
B
Brors
Norbert
N
Gretz
Lutz
L
Edler
Carmen
C
Fischer
Oliver
O
Hill
Meinolf
M
Thiemann
Bahram
B
Biglari
Saoussen
S
Karray
Ana
A
Martin-Villalba
D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010537:Peritoneum / Q000276:immunology / Q000473:pathology; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D000072377:Syk Kinase; D013864:Thioglycolates / Q000008:administration & dosage
D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D013864:Thioglycolates; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D020780:Matrix Metalloproteinase 9