However, in CCM, the cell wall component of gram-negative bacterial lipopolysaccharides, in conjunction with the intracellular adaptor protein complex defect resulting from the loss of function mutations of Krev interaction trapped protein 1, CCM2, and programmed cell death 10 genes, activates TLR4 in brain endothelial cells through TLR4-Mekk3-KLF1/4 signal transduction (84, 88). Here, TLR4 is linked to cerebral cavernous malformation.