Investigating the mechanisms of macrophage infiltration into the CNS during health and neurodegenerative tauopathy

Abstract

Peripheral-neuroimmune crosstalk (PNC) refers to the bidirectional immune interactions between peripheral tissues and the central nervous system. This occurs through structural and functional infiltration of peripheral macrophages past CNS borders and into the brain parenchyma. Using zebrafish and mice models, the role of macrophages in mediating PNC during health and neurodegenerative tauopathy was explored. Confocal live imaging techniques revealed that peripheral challenge via intraperitoneal LPS resulted in increased migration and infiltration of peripheral macrophages into the brain. Further analysis showed infiltration was associated with increased interactions between macrophages and endothelial cells through a specialized subgroup of cells termed ‘blood-vessel-associated macrophage’ (BVMac). Notably, BVMac numbers were elevated in the zebrafish A152T tauopathy model, and the 3xTg-AD mice model, suggesting that peripheral-neuroimmune interactions may be mediated by endothelial cell-macrophage crosstalk. To better explore this interaction, an in-vitro model was constructed by coculture of THP- 1-derived macrophages and human brain microvascular endothelial cells. Peripheral challenge induced structural and functional interactions between EC macrophages. In particular, IL34 was increased and was associated with increased functional resilience of EC proliferation after the scratch wound assay. Owing to these observations, this study addressed the role of IL34 in mediating EC-Macrophage interactions in the context of tauopathy. Using CRISPR-cas9 techniques, IL34 knockout reduced BVMac after peripheral challenge via i.p. LPS. This resulted in increased tau phosphorylation at site Thr181 associated with decreased cognitive performance and aggravated anxiety behaviors. For the first time, this study demonstrates that IL34 plays a vital role in mediating EC- macrophage interactions during PNC. Unraveling these complex mechanisms will greatly enhance our understanding of immune control in health and neurodegeneration.