Following acute inflammation in the rodent brain, one of the earliest events is the hepatic release of regulatory acute phase proteins (APP), which occurs before there is any evidence of an inflammatory response in the brain. We have found that one of the first APPs to be released from the liver in response to interleukin-1 beta (IL-1_-mediated experimental brain inflammation is the CXC chemokine, cytokine-induced neutrophil chemoattractant-1 (CINC-1). We now show that the hepatic chemokine response to injury is not restricted to the CXC chemokines and is a significant feature of the APR in a rodent model of spinal cord injury. CCL-2 and CINC-1 mRNA and protein, are rapidly expressed and released by the liver in response to injury. This hepatic chemokine response controls monocyte and neutrophil mobilisation and recruitment to the spinal cord and to the liver. Elevated CCL-2/CINC-1 mRNA and protein were observed in the liver as early as 2 h following a mild compression injury in the spinal cord compared to a sham operation with laminectomy. Intravenous injection of anti-CINC-1 alone was sufficient to inhibit the mobilisation of blood neutrophils and to inhibit the recruitment neutrophils to the injured cord and to the liver. CINC-1 inhibition also reduced lesion volume and preserved axon integrity. Thus hepatic chemokine production may regulate the CNS response to inflammation by controlling leukocyte recruitment to the injured spinal cord (See Figure 1).
A partial laminectomy was carried out at T8, and a controlled spinal cord compression injury was performed. Taqman RT-PCR (a, c) was used to assess the (a) CCL-2 and (c) CINC-1 mRNA levels in the liver 2 h and 4 h post-injury. Immunohistochemistry (b, d) was used to assess the number of activated kupffer cells/recruited monocytes (ED-1-positive cells) (b) and recruited neutrophils (d) in the liver post-spinal cord injury. Dashed red lines represent levels of mRNA and liver cells in naïve animals of the same age.