Microglia lacking a peroxisomal β-oxidation enzyme chronically alter their inflammatory profile without evoking neuronal and behavioral deficits
| Autor: | Philip Van Damme, Lien Beckers, Stijn Stroobants, Sander Beel, Ivana Geric, Myriam Baes, Rudi D'Hooge |
|---|---|
| Přispěvatelé: | Neurology |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
DYNAMICS Lipopolysaccharides Interleukin-4/administration & dosage medicine.medical_treatment Gene Expression Regulation/drug effects Stimulation Facial Nerve Diseases/complications β-Oxidation MULTIFUNCTIONAL PROTEIN-2 Microgliosis Neuronal Transmission lcsh:RC346-429 Functional Laterality Cell Proliferation/drug effects 0302 clinical medicine CX3CR1 Hand Strength/physiology Peroxisomal Multifunctional Protein-2 Microglia/drug effects Facial nerve axotomy Cells Cultured Medicine(all) ROLES Brain/drug effects Microglia Hand Strength General Neuroscience Microfilament Proteins LANGERHANS CELLS Brain DEGENERATION INSIGHTS medicine.anatomical_structure Neurology Exploratory Behavior/drug effects Peroxisomal Multifunctional Protein-2/deficiency Axotomy medicine.symptom Facial Nerve Diseases Life Sciences & Biomedicine CX3C Chemokine Receptor 1/metabolism EXPRESSION Inflammation/chemically induced mice Evoked Potentials Auditory Brain Stem/drug effects Immunology CX3C Chemokine Receptor 1 Conditional mouse model Inflammation Mice Transgenic Microfilament Proteins/metabolism 03 medical and health sciences Cellular and Molecular Neuroscience Calcium-Binding Proteins/metabolism In vivo medicine Evoked Potentials Auditory Brain Stem Peroxisomes Animals Immune response lcsh:Neurology. Diseases of the nervous system Cell Proliferation Behavior Science & Technology Oxidation business.industry Research Calcium-Binding Proteins Neurosciences Disease Models Animal Lipopolysaccharides/toxicity 030104 developmental biology MAINTENANCE Gene Expression Regulation Animals Newborn IL-34 Exploratory Behavior Neurosciences & Neurology Interleukin-4 business Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neuroinflammation, Vol 16, Iss 1, Pp 1-15 (2019) Journal of Neuroinflammation |
| DOI: | 10.1186/s12974-019-1442-3 |
| Popis: | Background 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. 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. 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. 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. Results We 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. Conclusion Our 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. Electronic supplementary material The online version of this article (10.1186/s12974-019-1442-3) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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