Endothelial TLR4 and the microbiome drive cerebral cavernous malformations

Abstract

Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3–KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment. Lipopolysaccharide derived from gut bacteria can accelerate the formation of cerebral cavernous malformations by activating TLR4 on endothelial cells, and polymorphisms that increase expression of the genes encoding TLR4 or its co-receptor CD14 are associated with higher CCM lesion burden in humans. Cerebral cavernous malformations (CCMs) are malformations of the vascular system, seen mainly in the brain where they can cause haemorrhagic stroke and seizures. CCMs arise from loss-of-function mutations in components of a complex that negatively regulates MEKK3–KLF2/4 signalling and Rho/ROCK signalling in brain endothelial cells. Mark Kahn and colleagues now identify upstream regulators that activate this pathway in brain endothelial cells. They find that lipopolysaccharide derived from gut bacteria can accelerate CCM formation by activating TLR4 on endothelial cells. The authors further show that polymorphisms in the TLR4 gene or CD14, the gene encoding its co-receptor, are associated with higher CCM lesion burden in humans. These findings suggest that the gut microbiome and TLR4 are important drivers of CCMs and represent potential therapeutic targets.

Cite this article

Tang, A., Choi, J., Kotzin, J. et al. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature 545, 305–310 (2017). https://doi.org/10.1038/nature22075

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