Nucleotide-binding and oligomerization domain 2 (NOD2) knock-in mice carrying a mutation associated with Blau syndrome show reduced amounts of NOD2 protein and decreased muramyl dipeptide (MDP)-induced inflammatory responses
Journal of Immunology(2013)
Abstract
Abstract Blau syndrome is an autosomal dominant disorder caused by mutations in NOD2 and characterized by arthritis, dermatitis and uveitis. NOD2 binds MDP and activates NF-kB and MAPK signaling cascades. Prior in vitro studies reported that NOD2 containing Blau mutations caused enhanced activation of NF-kB, suggesting a gain of function in mutated NOD2 caused Blau syndrome. We tested this hypothesis in vivo by creating a knock-in mouse where a point mutation resulted in a change of arginine [R] to glutamine [Q] at position 314 (R314Q) of NOD2 (position 314 in mice corresponds to 334 in humans). R314Q heterozygous (+/m) and homozygous (m/m) mice did not spontaneously develop arthritis or dermatitis. Bone marrow derived macrophages (BMDM) from R314Q mice showed a reduction in NOD2 protein levels compared to wild type (WT) mice despite comparable amounts of NOD2 mRNA. MDP treatment of BMDM showed reduced activation of NF-kB and p38 MAPK in +/m and m/m compared to WT mice that correlated with the copy number of mutated NOD2, with the greatest reduction in m/m mice. In response to ip MDP, reduced levels of IL-6 and KC were detected in the serum of +/m and m/m mice, also in manner correlating with the copy number of the mutation. These data indicate that R314Q-NOD2 mice do not demonstrate a gain of function of the NOD2 pathway. Rather, R314Q causes a deficiency of NOD2 and raises the possibility that Blau syndrome may fall within the spectrum of an immunodeficiency disease.
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Key words
nod2 protein,inflammatory responses,blau syndrome show,muramyl dipeptide,nucleotide-binding
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