Our data support the notion that infiltrating and resident macrophages in the liver may critically modulate CNS and systemic inflammation by shaping the hepatic response to circulating or widely distributed molecules that may be infectious, toxic, or exogenous.ДЄ possible route through which the brain may affect liver function may simply be a drainage of effector molecules into circulation, albeit even at a trace level, to initiate systemic inflammation, rather than direct brain to liver signaling. Using zebrafish, we were able to directly capture the dynamic changes in macrophages occurring in the body after a focal brain challenge and found the liver to be the most prominent target peripheral organ for immune infiltration. We employed the zebrafish because it offers unparalleled access to in vivo tracking and manipulation of molecular and cellular processes in the intact whole vertebrate animal from brain to peripheral organs, which are largely conserved from zebrafish to humanВ ( Santoriello and Zon, 2012). To this end, we investigated if a brain perturbation triggering inflammation, using a brain-localized LPS microinjection as an experimental means, could trigger a peripheral organ response mediated by macrophages. To investigate components of communication between the brain and periphery, we hypothesized that macrophages, key innate immune cells, capable of long-range migration and signalingВ ( Eom and Parichy, 2017), could act as mediators of brain-periphery communication. The ability to track the cellular and molecular processes from the brain to the liver in vivo provides a direct means to understand the brain-liver association. However, the underlying mechanisms that may link brain inflammation with liver impairment remain unclear. A few recent studies have implicated a systemic, albeit most prominently a hepatic response to CNS inflammation due to CNS trauma or injury in mammalsВ ( Campbell et al., 2005 Anthony et al., 2012). Interestingly, liver damage and neutrophil recruitment to the liver are common features in sepsis-related injuryВ ( McDonald et al., 2012) and several central nervous system (CNS) pathologiesВ ( Campbell et al., 2010 Estrada et al., 2019), including traumatic brain injury, multiple sclerosis, and AlzheimerвЂ™s disease. Whether a diseased or injured brain transmits signals to the periphery to activate a response is an interesting prospect in understanding brain-periphery communication, but remains underexplored. Understanding how the brain engages the periphery at times of danger may offer new perspectives for detecting and treating brain pathologies. These results highlight the possibility for circulation of brain-derived substances to serve as a rapid mode of communication from brain to the liver. 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. 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. 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. Many brain pathologies are associated with liver damage, but a direct link has long remained elusive.

Periphery 3 has it leaked