Phagocytosis of apoptotic inflammatory cells downregulates microglial chemoattractive function and migration of encephalitogenic T cells.
Apoptosis of autoaggressive T cells in the central nervous system (CNS) and subsequent phagocytosis by microglia is probably crucial in the rapid resolution of the inflammatory infiltrate in T cell mediated neuroinflammatory diseases. In addition to mere clearance, phagocytosis of apoptotic leukocytes results in the downregulation of different microglial immune functions. Chemoattractive functions of Lewis rat microglia and secretion of chemokines and matrix-metalloproteinases (MMPs) were investigated after phagocytosis of apoptotic T cells in vitro. In a modified Boyden chamber assay migration of encephalitogenic T cells toward LPS-stimulated microglial supernatants after phagocytosis of apoptotic thymocytes was reduced by 24.9% in comparison to interaction with viable target cells (P < 0.001). Phagocytosis of apoptotic cells downregulated CC-chemokine ligand (CCL)-5-secretion by LPS-stimulated microglia by 66.2% (P < 0.001), whereas there was only a trend toward decreased CCL2-secretion. As determined by gelatinase-zymography, secretion of MMP-9 by microglia was decreased after phagocytosis of apoptotic cells, whereas MMP-2 secretion was not altered. These mechanisms may reduce further recruitment of pathogenic inflammatory cells into the CNS-lesion and thus contribute to the active resolution of the inflammatory infiltrate and termination of the autoimmune attack.
Chan
Andrew
A
Institute for MS-Research, Medical Faculty, University of Göttingen and Gemeinnützige Hertie-Stiftung, Göttingen, Germany. a.chan@med.uni-goettingen.de
Hummel
Vera
V
Weilbach
Franz X
FX
Kieseier
Bernd C
BC
Gold
Ralf
R
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics; D018925:Chemokines / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects; D004660:Encephalitis / Q000473:pathology*; D018093:Gelatinases / Q000378:metabolism; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000502:physiology*
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018925:Chemokines; D008070:Lipopolysaccharides; D018093:Gelatinases