Liver Kupffer cells control the magnitude of the inflammatory response in the injured brain and spinal cord.
The CNS inflammatory response is regulated by hepatic chemokine synthesis, which promotes leukocytosis and facilitates leukocyte recruitment to the site of injury. To understand the role of the individual cell populations in the liver during the hepatic response to acute brain injury, we selectively depleted Kupffer cells (KC), using clodronate-filled liposomes, and assessed the inflammatory response following a microinjection of IL-1beta into the rat brain or after a compression injury in the spinal cord. We show by immunohistochemistry that KC depletion reduces neutrophil infiltration into the IL-1beta-injected brain by 70% and by 50% into the contusion-injured spinal cord. qRT-PCR analysis of hepatic chemokine mRNA expression showed that chemokine expression in the liver after brain injury is not restricted to a single cell population. In non-depleted rats, CXCL-10, IL-1beta, CCL-2, and MIP-1alpha mRNAs were increased up to sixfold more than in KC depleted rats. However, CXCL-1 and MIP-1beta were not significantly affected by KC depletion. The reduction in chemokine mRNA expression by the liver was not associated with decreased neutrophil mobilisation as might have been expected. These findings suggest that in response to CNS injury, KC mediated mechanisms are responsible for increasing neutrophil entry to the site of CNS injury, but that neutrophil mobilisation is dependent on other non-KC mediated events. However, the suppression of KC activity may prevent secondary damage after acute brain injury.
Campbell
Sandra J
SJ
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
Zahid
Imran
I
Losey
Patrick
P
Law
Shing
S
Jiang
Yanyan
Y
Bilgen
Mehmet
M
van Rooijen
Nico
N
Morsali
Damineh
D
Davis
Andrew E M
AE
Anthony
Daniel C
DC
D000704:Analysis of Variance; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001930:Brain Injuries / Q000150:complications*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004002:Clodronic Acid / Q000494:pharmacology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology*; D053583:Interleukin-1beta / Q000494:pharmacology; D007728:Kupffer Cells / Q000187:drug effects / Q000502:physiology*; D008081:Liposomes / Q000008:administration & dosage; D008297:Male; D009187:Myelitis / Q000209:etiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013119:Spinal Cord Injuries / Q000150:complications*; D013997:Time Factors
D050071:Bone Density Conservation Agents; D018925:Chemokines; D053583:Interleukin-1beta; D008081:Liposomes; D012333:RNA, Messenger; D004002:Clodronic Acid