Macrophage-specific IL-1β ablation rescues tau burden via the reduction of macrophage infiltration into the central nervous system after systemic challenge

Systemic inflammation can initiate neuroinflammation, leading to abnormal tau hyperphosphorylation, a critical factor in the development of tau pathology and cognitive decline. Despite these associations, the mechanisms driving this process remain largely unexplored. This study demonstrated that sources of interleukin-1β, specifically in macrophages, act as a key mediator of peripheral-neuroimmune crosstalk. In this study, systemic challenge was simulated in the zebrafish model via fin amputation (sterile inflammation) and intraperitoneal (i.p.) LPS (lipopolysaccharide) administration (non-sterile inflammation), both of which resulted in significant neuroinflammation characterized by macrophage infiltration and elevated IL-1β expression. Using CRISPR-cas9, we generated a novel macrophage-specific IL1β knockout (KO) model, where IL1β was selectively ablated in macrophages only. Notably, macrophage-specific IL-1β KO zebrafish exhibited significantly reduced neuroinflammation, as indicated by decreased microglial and astrocytic activation, along with diminished tau phosphorylation at the Ser396 site after fin amputation. Behavioral assessments further revealed that IL-1β KO zebrafish showed improved cognitive performance and reduced anxiety, highlighting the potential of targeted IL-1β inhibition to enhance cognitive outcomes and emotional well-being. Interestingly, fin amputation induced significant macrophage infiltration into the CNS via lyve1 + lymphatic vessels. These findings underscore the crucial role of macrophage-derived IL-1β in mediating neuroinflammation and its impact on tau pathology and cognitive function. This study highlights the therapeutic potential of targeting IL-1β in macrophages, paving the way for interventions aimed at mitigating neurodegenerative diseases and related cognitive disorders.