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TRIM21 Mitigates Human Lung Microvascular Endothelial Cells ’ In ﬂ ammatory Responses to LPS

Endothelial cell (EC) in ﬂ ammation is regarded as an important pathogenic feature of many in ﬂ ammatory diseases, including acute lung injury and sepsis. An increase in EC in ﬂ ammation results in neutrophil in ﬁ ltration from the blood to the site of in ﬂ ammation, further promoting EC permeability. The ubiquitin E3 ligase TRIM21 has been implicated in human disorders; however, the roles of TRIM21 in endothelial dysfunction and acute lung injury have not been reported. Here, we reveal an antiin ﬂ ammatory property of TRIM21 in a mouse model of acute lung injury and human lung microvascular ECs. Overexpression of TRIM21 by lentiviral vector infection effectively dampened LPS-induced neutrophil in ﬁ ltration, cytokine release, and edema in mice. TRIM21 inhibited human lung microvascular endothelial cell in ﬂ ammatory responses as evidenced by attenuation of the NF- k B pathway, release of IL-8, expression of intercellular adhesion molecules, and adhesion of monocytes to ECs. Furthermore, we demonstrated that TRIM21 was predominantly degraded by an increase in its monoubiquitination andlysosomaldegradationafterin ﬂ ammatory stimuli. Thus, inhibition of vascular endothelial in ﬂ ammation by TRIM21 provides a novel therapeutic target to lessen pulmonary in ﬂ ammation.