Microglia and the early phase of immune surveillance in the axotomized facial motor nucleus: Impaired microglial activation and lymphocyte recruitment but no effect on neuronal survival or axonal regeneration in macrophage-colony stimulating factor-deficient mice

Activation of microglia is among the first cellular changes in the injured CNS. However, little is known about their specific contribution to secondar y damage or repair processes in neighboring neurons and nonneuronal cells o r to the immune surveillance of the damaged tissue. Animal models with defe ctive microglial response such as osteopetrosis provide an approach to expl ore these effects. Osteopetrosis (op) is an autosomal recessive mutation wi th a complete deficiency of the macrophage-colony stimulating factor (MCSF; CSF-1), an important mitogen for brain microglia. In the current study we examined the effects of this MCSF deficiency on the microglial reaction and the overall cellular response to nerve injury in the mouse axotomized faci al motor nucleus. In the brain, MCSF receptor immunoreactivity was found on ly on microglia and was strongly up-regulated following injury. MCSF defici ency led to a failure of microglia to show a normal increase in early activ ation markers (thrombospondin, MCSF receptor, alphaM beta2- and alpha5 beta 1-integrins), to spread on the surface of axotomized motoneurons, and to pr oliferate after injury. Early recruitment of CD3(+) T-lymphocytes to the fa cial nucleus 24 hours after injury was reduced by 60%. In contrast, the neu ronal and astrocyte response was not affected. There was a normal increase in the neuropeptides calcitonin gene-related peptide and galanin, neuronal c-JUN, and NADPH-diaphorase and a decrease in choline acetyltransferase and acetylcholinesterase. Astrocyte glial fibrillary acidic protein immunoreac tivity also showed a normal increase. There was a normal influx of macropha ges and granulocytes into the injured facial nerve. Synaptic stripping, neu ronal survival, and speed of axonal regeneration were also not affected. Th e current results show a strong, selective effect of MCSF on the early acti vation of microglia and, indirectly, on lymphocyte recruitment. This early phase of microglial activation appears not to be involved in the process of repair following peripheral nerve injury. However, it is important in the initiation of inflammatory changes in the brain and in the interaction with the immune system. J. Comp. Neurol. 436:182-201, 2001. (C) 2001 Wiley-Liss , Inc.