J Neurosci 2002 Jul 15;22(14):6071-82
Basu A, Krady JK, O'Malley M, Styren SD, DeKosky ST, Levison SW.
Department of Neuroscience and Anatomy, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, and Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
Interleukin-1 (IL-1) is induced immediately after insults to the brain, and elevated levels of IL-1 have been strongly implicated in the neurodegeneration that accompanies stroke, Alzheimer's disease, and multiple sclerosis.
In animal models, antagonizing IL-1 has been shown to reduce cell death; however, the basis for this protection has not been elucidated.
Here we analyzed the response to penetrating brain injury in mice lacking the type 1 IL-1 receptor (IL-1R1) to determine which cellular and molecular mediators of tissue damage require IL-1 signaling.
At the cellular level, fewer amoeboid microglia/macrophages appeared adjacent to the injured brain tissue in IL-1R1 null mice, and those microglia present at early postinjury intervals retained their resting morphology.
Astrogliosis also was mildly abrogated.
At the molecular level, cyclooxygenase-2 (Cox-2) and IL-6 expression were depressed and delayed.
Interestingly, basal levels of Cox-2, IL-1, and IL-6 were significantly lower in the IL-1R1 null mice.
In addition, stimulation of vascular cell adhesion molecule-1 mRNA was depressed in the IL-1R1 null mice, and correspondingly, there was reduced diapedesis of peripheral macrophages in the IL-1R1 null brain after injury.
This observation correlated with a reduced number of Cox-2(+) amoeboid phagocytes adjacent to the injury.
In contrast, several molecular aspects of the injury response were normal, including expression of tumor necrosis factor-alpha and the production of nerve growth factor.
Because antagonizing IL-1 protects neural cells in experimental models of stroke and multiple sclerosis, our data suggest that cell preservation is achieved by abrogating microglial/macrophage activation and the subsequent self-propagating cycle of inflammation.