title: CXCR2 signaling protects oligodendrocyte progenitor cells from IFN-γ/CXCL10-mediated apoptosis.
abstract: Infiltration of activated lymphocytes into the central nervous system (CNS) is potentially harmful by damaging resident cells through release of cytokines. Among these is IFN-γ that is secreted by activated natural killer (NK) cells and T lymphocytes and can exert a cytotoxic effect on resident glial populations including oligodendrocytes. Here we show that treatment of mouse oligodendrocyte progenitor cell (OPC)-enriched cultures with IFN-γ resulted in a dose-dependent increase in apoptosis. IFN-γ-induced apoptosis is mediated, in part, through induction of the CXC chemokine ligand 10 (CXCL10; IP-10) from cultured OPCs. Treatment of OPCs with CXCL10 resulted in cell death in a concentration-dependent manner and IFN-γ-treatment of CXCL10-/- OPCs resulted in >50% reduction in cell death. Further, treatment of CXCR3-/- OPC cultures with either IFN-γ or CXCL10 resulted in reduced cell death supporting an important role for CXCL10 signaling in IFN-γ-mediated OPC apoptosis. Data is also provided demonstrating that signaling through CXCR2 protects either IFN-γ or CXCL10-treated OPC cultures from apoptosis and this effect is abolished in CXCR2-/- OPCs. CXCR2-mediated protection from apoptosis is associated with impaired cleavage of caspase 3 and elevated expression of the anti-apoptotic protein Bcl-2. These findings demonstrate a previously unappreciated role for CXCL10 in contributing to neuropathology by promoting oligodendrocyte apoptosis and emphasize the potential relevance in targeting CXCL10 in treating human demyelinating diseases including multiple sclerosis (MS).
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, USA.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Tirotta
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Lane
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000941:Antigens / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000172:deficiency / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D054357:Chemokine CXCL10; D007371:Interferon-gamma; D011509:Proteoglycans; D054367:Receptors, CXCR3; D023063:Receptors, Interleukin-8B; D000099216:Chondroitin Sulfate Proteoglycan 4; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse