Abstract
Objectives: Blau syndrome is a distinct class of autoinflammatory syndrome presenting with early-onset systemic granulomatosis. Blau syndrome-causing NOD2 mutations located in the central nucleotide-oligomerization domain induce ligand-independent basal NF-κB activation in an in vitro reporter assay. However, the precise role of this signaling on granuloma formation has not yet been clarified. Methods: Blau syndrome-causing NOD2 mutations were introduced into human monocytic THP-1 cells, and their morphological and molecular changes from parental cells were analyzed. Identified molecules with altered expression were examined in the patient’s lesional skin by immunostaining. Results: Although the production of proinflammatory cytokines was not altered without stimulation, mutant NOD2-expressing THP-1 cells attached persistently to the culture plate after stimulation with phorbol myristate acetate. Sustained surface ICAM-1 expression was observed in association with this phenomenon, but neither persistent ICAM-1 mRNA expression nor impaired ADAM17 mRNA expression was revealed. However, the transient induction of PDGF-B mRNA expression was specifically observed in stimulated THP-1 derivatives. In the granulomatous skin lesion of a Blau syndrome patient, ICAM-1 and PDGF-B were positively immunostained in NOD2-expressing giant cells. Conclusions: Sustained surface ICAM-1 expression and transient PDGF-B production by newly differentiating macrophages harboring mutant NOD2 might play a role in granuloma formation in Blau syndrome.
Highlights
Autoinflammatory diseases constitute a group of genetic disorders whose main clinical features are recurrent episodes of inflammatory lesions that can affect the skin, joints, bones, eyes, gastrointestinal tract and nervous system, in association with signs of systemic inflammation [1,2]
THP-1 cells were transfected by electroporation with either mock, FLAG-tagged WT, R334W or N670K mutant NOD2 cloned in the pIRES2-EGFP vector
NOD2 mRNA expression was only faintly observed in mock-transfected THP-1 cells, significant expression was observed in WT or mutant NOD2-transfected THP-1 derivatives
Summary
Autoinflammatory diseases constitute a group of genetic disorders whose main clinical features are recurrent episodes of inflammatory lesions that can affect the skin, joints, bones, eyes, gastrointestinal tract and nervous system, in association with signs of systemic inflammation [1,2]. This molecule is expressed intracellularly in antigen-presenting cells (APC) and recognizes muramyl dipeptide (MDP), the minimum common component of bacterial cell wall peptidoglycan, to form a complex with CARDcontaining serine/threonine kinase, RICK, and to induce immune responses through nuclear factor (NF)-κB activation [4,7]. While mutations in the LRR impairing MDP-dependent NF-κB activation are reportedly associated with Crohn’s disease (CD), Blau syndrome-associated NOD2 variants are localized in the NOD and show increased MDP-independent basal NF-κB activation, which is measured by an in vitro reporter assay using HEK293 cells [3,9,10,11]. The therapeutic effect for Blau syndrome of thalidomide, a potent immunomodulatory drug suppressing NF-κB activation, may suggest the role of NF-κB in the pathogenesis of this disease [13]
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