Drainage of inflammatory macromolecules from the brain to periphery targets the liver for macrophage infiltration
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Abstract
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.
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###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on June 15, 2020, follows.
Summary
In the manuscript by Yang et al. the authors investigate in zebrafish the effect of leakage of pro-inflammatory LPS form the brain in peripheral tissues. Using beautiful live imaging and genetic manipulations, they find that macrophages infiltrate the liver and their recruitment depends on myd88 and il34, thus underscoring the existence of rapid communication between the brain and the liver that may play a role in immune surveillance.
Two new reviewers and one reviewer that evaluated the previous version of this work agreed in that the manuscript has been greatly improved with substantial new data and an in-depth revision. Two key experimental manipulations, the knock down of myd88 and il34, are now …
###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on June 15, 2020, follows.
Summary
In the manuscript by Yang et al. the authors investigate in zebrafish the effect of leakage of pro-inflammatory LPS form the brain in peripheral tissues. Using beautiful live imaging and genetic manipulations, they find that macrophages infiltrate the liver and their recruitment depends on myd88 and il34, thus underscoring the existence of rapid communication between the brain and the liver that may play a role in immune surveillance.
Two new reviewers and one reviewer that evaluated the previous version of this work agreed in that the manuscript has been greatly improved with substantial new data and an in-depth revision. Two key experimental manipulations, the knock down of myd88 and il34, are now backed by stable loss of function mutations and several experiments have been strengthen with new or improved analyses. However, there are still two important experimental manipulations using morpholinos that have not been properly controlled. In addition, editorial changes are needed to better explain the use of LPS injections as an experimental tool.
Essential Revisions
The authors use morpholinos targeting csf3r and pu.1 expression and draw important conclusions based on those experiments. Given the inherent problems of morpholinos, particularly for inflammation studies, it is necessary to support the use of those reagents with stable mutants and/or additional controls. If mutants are not available or cannot be generated, the knockdown experiments may be further supported with rescue experiments and or F0 Criprs, in which case the significance of any findings related to those experiments should be tempered with an appropriate discussion of the caveats.
While brain injections of LPS can be a useful tool as used in this work, it is hardly a physiological condition. An editorial revision should address caveats and limitations, perhaps highlighting the use of this experimental approach as a tool.
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