**3.6 Occludin and MAPKs pathway**

MAPKs including extracellular signal-related kinases (ERK1/2), p38, and c-Jun N-terminal kinase [JNK] are a family of serine/threonine protein kinases [33]. Under the stimulation of various extracellular factors (such as inflammatory signals), MAPK kinase promotes the activation of nuclear proteins and transcription factors, and

regulates gene expression, differentiation, apoptosis and other processes. MAPK kinase is an important intracellular signal transduction that regulates various intracellular functions. Many studies have found that MAPK pathway activation can affect endothelial cell occludin expression and modification in physiological and pathological conditions: (1) Exposure of cerebral microvascular endothelial cells to lipopolysaccharide can affect the p38MAPK/JNK signaling pathway and MMP2 expression, thereby regulating the level of occludin protein in endothelial cells and leading to central nervous system inflammation and brain edema [34]; (2) ERK1/2 inhibits the activation of the NF-κB signaling pathway resulting in the increase of occludin and decrease of endothelial barrier permeability to protect the TJ barrier in human lung microvascular endothelial cells [35]; (3) after lipopolysaccharide stimulates human umbilical vein endothelial cells, it can promote the mRNA and protein expression of CXCL4 and its receptor CXCR3 activates the downstream p38 signaling pathway, thereby inhibiting the expression of occludin in endothelial cells, promoting endothelial cell apoptosis, and increasing endothelial cell permeability [36]; (4) exposure of human umbilical vein endothelial cells to γ-rays can promote the expression of MAPK pathway molecules p38, p53, p21, and p27, induce the activation of NF-κB signaling pathway, and inhibit the expression of occludin in endothelial cells, resulting in the increase of cell permeability, oxidative stress, nitrification, and inflammatory [37]; (5) in human brain microvascular endothelial cells, reduction of occludin can upregulate PI3K/AKT and ERK signaling pathways, and promote cytokine secretion, inflammatory factor activation, and apoptosis protein expression. However, overexpression of occludin can inhibit endothelial cell apoptosis and inflammation [25]. In conclusion, the MAPK signaling pathway is closely related to the regulation of occludin.
