NLRP3-dependent lipid droplet formation contributes to posthemorrhagic hydrocephalus by increasing the permeability of the blood-cerebrospinal fluid barrier in the choroid plexus

Brain hemorrhage: Causes of fluid build-up on the brainInhibiting a key inflammatory protein and thereby protecting the blood-brain barrier following brain hemorrhage may prevent the build-up of fluid on the brain (hydrocephalus). Using rat models and cell cultures, Yujie Chen and Hua Feng at the Third Military Medical University in Chongqing, China, and co-workers examined how posthemorrhagic hydrocephalus occurs. They found that the acute inflammatory response activated immediately after a brain hemorrhage, which is driven by a critical protein complex involved in innate immunity called the NLRP3 inflammasome, triggers the formation of lipid droplets in the choroid plexus, a part of the brain adjacent to the blood-brain barrier. The lipid droplets interact with mitochondria, increasing the release of reactive oxygen species and damaging the blood-brain barrier. This barrier dysfunction triggers hydrocephalus. Blocking NLRP3 activity improved the function of the barrier following hemorrhage. Hydrocephalus is a severe complication that can result from intracerebral hemorrhage, especially if this hemorrhage extends into the ventricles. Our previous study indicated that the NLRP3 inflammasome mediates cerebrospinal fluid hypersecretion in the choroid plexus epithelium. However, the pathogenesis of posthemorrhagic hydrocephalus remains unclear, and therapeutic strategies for prevention and treatment are lacking. In this study, an Nlrp3(-/-) rat model of intracerebral hemorrhage with ventricular extension and primary choroid plexus epithelial cell culture were used to investigate the potential effects of NLRP3-dependent lipid droplet formation and its role in the pathogenesis of posthemorrhagic hydrocephalus. The data indicated that NLRP3-mediated dysfunction of the blood-cerebrospinal fluid barrier (B-CSFB) accelerated neurological deficits and hydrocephalus, at least in part, through the formation of lipid droplets in the choroid plexus; these lipid droplets interacted with mitochondria and increased the release of mitochondrial reactive oxygen species that destroyed tight junctions in the choroid plexus after intracerebral hemorrhage with ventricular extension. This study broadens the current understanding of the relationship among NLRP3, lipid droplets and the B-CSFB and provides a new therapeutic target for the treatment of posthemorrhagic hydrocephalus. Strategies to protect the B-CSFB may be effective therapeutic approaches for posthemorrhagic hydrocephalus.

Automated summary

Chinese researchers at the Third Military Medical University in Chongqing have discovered that inhibiting the NLRP3 inflammasome protein can prevent the build-up of fluid on the brain after a hemorrhage. This protein complex triggers the formation of lipid droplets in the choroid plexus, damaging the blood-brain barrier and leading to hydrocephalus. Blocking NLRP3 activity improves the function of the barrier and could be a new therapeutic target for posthemorrhagic hydrocephalus.