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

Nagyőszi, Péter and Nyúl-Tóth, Ádám and Fazakas, Csilla and Wilhelm, Imola Mária and Kozma, Mihály and Molnár, Judit and Haskó, János and Krizbai, István Adorján (2015) Regulation of NOD-like receptors and inflammasome activation in cerebral endothelial cells. JOURNAL OF NEUROCHEMISTRY. ISSN 0022-3042

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Abstract

Cerebral endothelial cells (CECs) 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 CECs 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 (NLRs) - including NOD1, NOD2, NLRC4, NLRC5, NLRP1, NLRP3, NLRP5, NLRP9, NLRP10, NLRP12, NLRA, and NLRX - in human brain endothelial cells. Inflammatory cytokines, such as interferon-gamma, tumor necrosis factor-alpha, and IL-1beta had stimulatory effects on the transcription of many of these receptors. Expression of key inflammasome components (NOD2, NLRP3, and caspase 1) along with caspase-cleaved interleukins IL-1beta 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-1beta secretion in a caspase- and ERK1/2 kinase-dependent manner. Our findings demonstrate that NLRs 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. Here, 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-1beta 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-1beta secretion in a caspase (i.e., inflammasome)- and ERK1/2-dependent manner.

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