Regulation of NOD‐like receptors and inflammasome activation in cerebral endothelial cells

Abstract

Cerebral endothelial cells (CEC s) forming the blood–brain barrier are at the interface of the immune and the central nervous systems and thus may play an important role in the functional integration of the two systems. Here, we investigated how CEC s recognize and respond to pathogen‐ and damage‐associated molecular patterns to regulate the functions of the neurovascular unit. First we detected the expression of several NOD‐like receptors (NLR s) – including NOD 1, NOD 2, NLRC 4, NLRC 5, NLRP 1, NLRP 3, NLRP 5, NLRP 9, NLRP 10, NLRP 12, NLRA, and NLRX – in human brain endothelial cells. Inflammatory cytokines, such as interferon‐γ, tumor necrosis factor‐α, and IL‐1β had stimulatory effects on the transcription of many of these receptors. Expression of key inflammasome components (NOD 2, NLRP 3, and caspase 1) along with caspase‐cleaved interleukins IL‐1β and IL‐33 could be induced by priming with lipopolysaccharide and activation with muramyl dipeptide. In addition, combined treatment with lipopolysaccharide and muramyl dipeptide resulted in IL‐1β secretion in a caspase‐ and ERK 1/2 kinase‐dependent manner. Our findings demonstrate that NLR s and inflammasomes can be activated in cerebral endothelial cells, which may confer a yet unexplored role to the blood–brain barrier in neuroimmune and neuroinflammatory processes. imageHere, we show that cerebral endothelial cells (CECs), the main components of the blood–brain barrier, express several NOD (nucleotide‐binding oligomerization domain‐containing protein)‐like receptors and are able to assemble functional inflammasomes. Expression of key inflammasome components (NOD2, NLRP3, and caspase 1) along with caspase‐cleaved interleukins IL‐1β and IL‐33 can be induced in CECs by priming with lipopolysaccharide (LPS) and activation with muramyl dipeptide (MDP). Combined treatment with LPS and MDP results in IL‐1β secretion in a caspase (i.e., inflammasome)‐ and ERK1/2‐dependent manner.