Peripheral NOD-like receptor deficient inflammatory macrophages trigger neutrophil infiltration into the brain disrupting daytime locomotion.

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 il1ß, tnfα, cxcl8a) in the absence of microglia co-opt neutrophils to infiltrate the brain, thereby potentially enabling local circuitry modulation affecting daytime locomotion.

Zebrafish harbor diverse intestinal macrophage populations including a subset intimately associated with enteric neural processes.

Intestinal macrophages are essential for gut health but remain understudied outside of human and mouse systems. Here, we establish zebrafish as a powerful model that provides superior imaging capabilities for whole-gut analysis along all dimensions (anterior-posterior and center-outer axes) for dissecting macrophage biology in gastrointestinal health and disease. We utilized high-resolution imaging to show that the zebrafish gut contains bona fide muscularis and mucosal macrophages, as well as surprisingly large subsets intimately associated with enteric neural processes. Interestingly, most muscularis macrophages span multiple gut layers in stark contrast to their mammalian counterparts typically restricted to a single layer. Using macrophage-deficient irf8 zebrafish, we found a depletion of muscularis but not mucosal macrophages, and that they may be dispensable for gross intestinal transit in adults but not during development. These characterizations provide first insights into intestinal macrophages and their association with the enteric nervous system from development to adulthood in teleosts.

Drainage of inflammatory macromolecules from the brain to periphery targets the liver for macrophage infiltration.

Many brain pathologies are associated with liver damage, but a direct link has long remained elusive. Here, we establish a new paradigm for interrogating brain-periphery interactions by leveraging zebrafish for its unparalleled access to the intact whole animal for in vivo analysis in real time after triggering focal brain inflammation. Using traceable lipopolysaccharides (LPS), we reveal that drainage of these inflammatory macromolecules from the brain led to a strikingly robust peripheral infiltration of macrophages into the liver independent of Kupffer cells. We further demonstrate that this macrophage recruitment requires signaling from the cytokine IL-34 and Toll-like receptor adaptor MyD88, and occurs in coordination with neutrophils. These results highlight the possibility for circulation of brain-derived substances to serve as a rapid mode of communication from brain to the liver. Understanding how the brain engages the periphery at times of danger may offer new perspectives for detecting and treating brain pathologies.