FTY720 attenuates accumulation of EMAP-II+ and MHC-II+ monocytes in early lesions of rat traumatic brain injury.
FTY720 (Fingolimod) is a novel type of immunosuppressive agent inhibiting lymphocyte egress from secondary lymphoid tissues thereby causing peripheral lymphopenia. FTY720 can inhibit macrophage infiltration into inflammatory lesions under pathological conditions. FTY720 has been clinically evaluated for prophylaxis of allograft rejection and treatment of multiple sclerosis, showing promising immunosuppressive effects. A robust inflammatory response after traumatic brain injury (TBI) plays an important role in the secondary or delayed injuries of TBI. Here we have investigated by immunohistochemistry in a rat TBI model the effects of FTY720 on early cell accumulation into the inflammatory tissue response and on expression of major histo-compatibility complex class II (MHC-II) and endothelial-monocyte activating polypeptide II (EMAP-II). Accumulation of MHC-II(+) or EMAP-II(+) cells became significant 1 day after injury and continuously increased during the early time periods. Further, double-staining experiments confirmed that the major cellular sources of MHC-II were reactive macrophages, however MHC-II(+) cells only constituted a small subpopulation of reactive macrophages. Immediately after TBI, peripheral administration of FTY720 (1 mg/kg in 1 mL saline, every second day) significantly attenuated the accumulation of MHC-II(+) macrophages from Day 1 to 4 and significantly attenuated the accumulation of EMAP-II(+) macrophages/microglia at Day 4. Our findings show that FTY720 attenuates early accumulation of EMAP-II(+) and MHC-II(+) reactive monocytes following TBI, indicating that FTY720 might be a drug candidate to inhibit brain inflammatory reaction following TBI.
Zhang
Zhiyuan
Z
Institute of Brain Research, University of Tuebingen, Calwer Strasse 3, D-72076 Tuebingen, Germany.
Zhang
Zhiren
Z
Fauser
Uwe
U
Artelt
Matthias
M
Burnet
Michael
M
Schluesener
Hermann J
HJ
D000818:Animals; D001930:Brain Injuries / Q000209:etiology / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis*; D000068876:Fingolimod Hydrochloride; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009000:Monocytes / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D011409:Propylene Glycols / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000096:biosynthesis*; D051381:Rats; D011917:Rats, Inbred Lew; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors
D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D009363:Neoplasm Proteins; D011409:Propylene Glycols; D016601:RNA-Binding Proteins; C077219:small inducible cytokine subfamily E, member 1; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine