Abstract
BackgroundMicroglia play a central role in most neurological disorders, but the impact of microgliosis on brain environment and clinical functions is not fully understood. Mice lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develop a fatal disorder characterized by motor problems similar to the milder form of MFP2 deficiency in humans. The hallmark of disease in mice is the chronic proliferation of microglia in the brain, but molecular pathomechanisms that drive rapid clinical deterioration in human and mice remain unknown. In the present study, we identified the effects of specific deletion of MFP2 from microglia in the brain on immune responses, neuronal functioning, and behavior.MethodsWe created a novel Cx3cr1-Mfp2−/− mouse model and studied the impact of MFP2 deficiency on microglial behavior at different ages using immunohistochemistry and real-time PCR. Pro- and anti-inflammatory responses of Mfp2−/− microglia were assessed in vitro and in vivo after stimulation with IL-1β/INFγ and IL-4 (in vitro) and LPS and IL-4 (in vivo). Facial nerve axotomy was unilaterally performed in Cx3cr1-Mfp2−/− and control mice, and microglial functioning in response to neuronal injury was subsequently analyzed by histology and real-time PCR. Finally, neuronal function, motor function, behavior, and cognition were assessed using brainstem auditory evoked potentials, grip strength and inverted grid test, open field exploration, and passive avoidance learning, respectively.ResultsWe found that Mfp2−/− microglia in a genetically intact brain environment adopt an inflammatory activated and proliferative state. In addition, we found that acute inflammatory and neuronal injury provoked normal responses of Mfp2−/− microglia in Cx3cr1-Mfp2−/− mice during the post-injury period. Despite chronic pro-inflammatory microglial reactivity, Cx3cr1-Mfp2−/− mice exhibited normal neuronal transmission, clinical performance, and cognition.ConclusionOur data demonstrate that MFP2 deficiency in microglia causes intrinsic dysregulation of their inflammatory profile, which is not harmful to neuronal function, motor function, and cognition in mice during their first year of life.
Highlights
Microglia play a central role in most neurological disorders, but the impact of microgliosis on brain environment and clinical functions is not fully understood
Generation of microglia/monocyte-specific Cx3cr1-Mfp2−/− mice In order to investigate whether inactivation of peroxisomal β-oxidation in microglia impacts on microglial behavior and may contribute to the neuropathology that we observed in Mfp2−/− mice, we generated a microglia/ monocyte-specific knockout, by crossbreeding Cx3cr1Cre mice [20] with floxed Mfp2 mice [2]
Because reliable antibodies for immunohistochemical detection of multifunctional protein-2 (MFP2) are not available [30], we confirmed the recombination of Mfp2 in microglia of Cx3cr1-Mfp2−/ − mice using transcript analysis on magnetic-activated cell sorting (MACS)-isolated microglia
Summary
Microglia play a central role in most neurological disorders, but the impact of microgliosis on brain environment and clinical functions is not fully understood. Mice lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develop a fatal disorder characterized by motor problems similar to the milder form of MFP2 deficiency in humans. We identified the effects of specific deletion of MFP2 from microglia in the brain on immune responses, neuronal functioning, and behavior. Methods: We created a novel Cx3cr1-Mfp2−/− mouse model and studied the impact of MFP2 deficiency on microglial behavior at different ages using immunohistochemistry and real-time PCR. Despite chronic pro-inflammatory microglial reactivity, Cx3cr1-Mfp2−/− mice exhibited normal neuronal transmission, clinical performance, and cognition. Inactivation of peroxisomal β-oxidation by the loss of multifunctional protein-2 (MFP2) in human and mice causes a fatal neuropathological phenotype [1,2,3,4]. The pathomechanisms of disease and role of MFP2 in the brain remain elusive in human and mice
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