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Peripheral NOD-like receptor deficient inflammatory macrophages trigger neutrophil infiltration into the brain
Victoria Kwon1, Peiwen Cai1, Cameron T Dixon1
1Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Abstract:
Inflammation is known to disrupt normal behavior, yet the underlying neuroimmune interactions remain elusive. Here, we investigated whether inappropriate macrophage-evoked inflammation alters CNS control of daily-life animal locomotion using a set of zebrafish mutants selected for specific macrophage dysfunction and microglia deficiency. Large-scale genetic and computational analyses revealed that NOD-like receptor nlrc3l mutants are capable of normal motility and visuomotor response, but preferentially swim less in the daytime, suggesting possible low motivation rather than physical impairment. Examining their brain activities and structures implicates impaired dopaminergic descending circuits, where neutrophils abnormally infiltrate. Furthermore, neutrophil depletion recovered daytime locomotion. Restoring wild-type macrophages reversed behavioral and neutrophil aberrations, while three other microglia-lacking mutants failed to phenocopy nlrc3l mutants. Overall, we reveal how peripheral inflammatory macrophages with elevated pro-inflammatory cues (including il1β, tnfα, cxcl8a) in the absence of microglia co-opt neutrophils to infiltrate the brain, thereby potentially enabling local circuitry modulation affecting daytime locomotion.
Insights
Inflammatory macrophages, when lacking microglia, can impair daytime locomotion in zebrafish by recruiting neutrophils to the brain. Restoring normal macrophages or depleting neutrophils resolves this behavioral deficit.
Area of Science:
- Neuroimmunology
- Behavioral Neuroscience
- Zebrafish Models
Background:
- Inflammation disrupts behavior, but neuroimmune mechanisms are unclear.
- Macrophage dysfunction and microglia deficiency are implicated in altered CNS control.
Purpose of the Study:
- Investigate how macrophage-evoked inflammation affects CNS control of animal locomotion.
- Utilize zebrafish mutants with macrophage or microglia defects.
Main Methods:
- Genetic screening of zebrafish mutants for macrophage dysfunction and microglia deficiency.
- Large-scale genetic and computational analyses of locomotion and brain activity.
- Neutrophil depletion and macrophage restoration experiments.
Main Results:
- NOD-like receptor nlrc3l mutants showed reduced daytime locomotion, indicating low motivation.
- Impaired dopaminergic circuits and neutrophil infiltration were observed in nlrc3l mutants.
- Neutrophil depletion and wild-type macrophage restoration normalized behavior and neutrophil infiltration.
Conclusions:
- Peripheral inflammatory macrophages, in the absence of microglia, recruit neutrophils to the brain.
- This neuroinflammatory process modulates local circuitry, affecting daytime locomotion.
- Specific neuroimmune interactions involving macrophages, neutrophils, and dopaminergic circuits are crucial for regulating daily activity patterns.
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