Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor gamma in microglia/macrophages.
OBJECTIVE
Phagocytosis is necessary to eliminate the hematoma after intracerebral hemorrhage (ICH); however, release of proinflammatory mediators and free radicals during phagocyte activation is toxic to neighboring cells, leading to secondary brain injury. Promotion of phagocytosis in a timely and efficient manner may limit the toxic effects of persistent blood products on surrounding tissue and may be important for recovery after ICH.


METHODS
Intrastriatal blood injection in rodents and primary microglia in culture exposed to red blood cells were used to model ICH and to study mechanisms of hematoma resolution and phagocytosis regulation by peroxisome proliferator-activated receptor gamma (PPARgamma) in microglia/macrophages.


RESULTS
Our study demonstrated that the PPARgamma agonist, rosiglitazone, promoted hematoma resolution, decreased neuronal damage, and improved functional recovery in a mouse ICH model. Microglia isolated from murine brains showed more efficient phagocytosis in response to PPARgamma activators. PPARgamma activators significantly increased PPARgamma-regulated gene (catalase and CD36) expression, whereas reducing proinflammatory gene (tumor necrosis factor-alpha, interleukin-1beta, matrix metalloproteinase-9, and inducible nitric oxide synthase) expression, extracellular H(2)O(2) level, and neuronal damage. Phagocytosis by microglia was significantly inhibited by PPARgamma gene knockdown or neutralizing anti-CD36 antibody, whereas it was enhanced by exogenous catalase.


CONCLUSIONS
PPARgamma in macrophages acts as an important factor in promoting hematoma absorption and protecting other brain cells from ICH-induced damage.
Zhao
Xiurong
X
Stroke Program, Department of Neurology, University of Texas-Houston Medical School, Houston, TX 77030, USA.
Sun
Guanghua
G
Zhang
Jie
J
Strong
Roger
R
Song
Weitao
W
Gonzales
Nicole
N
Grotta
James C
JC
Aronowski
Jaroslaw
J
D000818:Animals; D000831:Animals, Newborn; D018955:CD36 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000150:complications / Q000473:pathology*; D016207:Cytokines / Q000187:drug effects; D004195:Disease Models, Animal; D020536:Enzyme Activators / Q000008:administration & dosage; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology; D006406:Hematoma / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives; D012720:Severity of Illness Index; D013997:Time Factors
C477819:15-deoxyprostaglandin J2; D018955:CD36 Antigens; D016207:Cytokines; D020536:Enzyme Activators; D047495:PPAR gamma; D006861:Hydrogen Peroxide; D052247:Nitric Oxide Synthase Type II; D015230:Prostaglandin D2