1.LRRK2 enhances Nod1/2-mediated inflammatory cytokine production by promoting Rip2 phosphorylation.
Protein & Cell 2017;8(1):55-66
The innate immune system is critical for clearing infection, and is tightly regulated to avert excessive tissue damage. Nod1/2-Rip2 signaling, which is essential for initiating the innate immune response to bacterial infection and ER stress, is subject to many regulatory mechanisms. In this study, we found that LRRK2, encoded by a gene implicated in Crohn's disease, leprosy and familial Parkinson's disease, modulates the strength of Nod1/2-Rip2 signaling by enhancing Rip2 phosphorylation. LRRK2 deficiency markedly reduces cytokine production in macrophages upon Nod2 activation by muramyl dipeptide (MDP), Nod1 activation by D-gamma-Glu-meso-diaminopimelic acid (iE-DAP) or ER stress. Our biochemical study shows that the presence of LRRK2 is necessary for optimal phosphorylation of Rip2 upon Nod2 activation. Therefore, this study reveals that LRRK2 is a new positive regulator of Rip2 and promotes inflammatory cytokine induction through the Nod1/2-Rip2 pathway.
Animals
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Cytokines
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genetics
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immunology
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HEK293 Cells
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Humans
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Immunity, Innate
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genetics
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Inflammation
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genetics
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immunology
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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genetics
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immunology
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Mice
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Mice, Knockout
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Nod1 Signaling Adaptor Protein
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genetics
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immunology
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Nod2 Signaling Adaptor Protein
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genetics
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immunology
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Phosphorylation
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genetics
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immunology
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Receptor-Interacting Protein Serine-Threonine Kinase 2
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genetics
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immunology
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Receptor-Interacting Protein Serine-Threonine Kinases
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genetics
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immunology
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Signal Transduction
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genetics
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immunology
2.Mutations of NOD2 gene and clinical features in Chinese Blau syndrome patients.
Wei WANG ; Min WEI ; Hongmei SONG ; Zhengqing QIU
Chinese Journal of Pediatrics 2014;52(12):896-901
OBJECTIVEBlau syndrome (BS), an autosomal dominant inherited autoinflammatory disease, is caused by NOD2 mutations. This study aimed to analyze NOD2 gene of suspected BS patients to make definite diagnosis, find NOD2 mutation types and clinical features of Chinese BS cases, and find some clinical indications to identify BS by comparing BS and non-BS cases.
METHODEighteen suspected BS children (7 boys and 11 girls, age of first visit was from 1 y 8 m to 9 y 6 m) who visited Peking Union Medical College Hospital from 2006 to 2014 and their parents's DNA were extracted from 4 ml blood specimens. PCR was performed for exon 4 of NOD2 and PCR products were purified by 2% gel electrophoresis and sequenced directly. Role of novel missense mutations in pathogenicity was analyzed by SIFT and sequencing NOD 2 of fifty normal controls. Clinical data of BS children diagnosed by NOD2 analysis were summarized and compared with the data of non-BS group.
RESULT(1) Twelve of eighteen suspected BS children were diagnosed as BS by NOD2 analysis, and the remaining 6 were excluded. Seven missense mutations were detected, 4 were reported before: c.1000C>T, p. Arg 334Trp; c.1001G>A, p. Arg334Gln; c.1538T>C, p. Met513Thr; c.1759C>T, p. Arg587Cys. Three novel mutations were found: c. 1147 G>C, p.Glu383Gln; c.1471A>T, p. Met491Leu; c.2006A>G, p.His669Arg. (2) Chronic symmetric arthritis and multi-joints periarticular hydatoncus, which were painless with fluctuation, were found in all 12 BS children with NOD2 mutations. Skin rash, chronic symmetric arthritis, and recurrent uveitis were identified in 7 patients. Three patients had no skin rash, while 1 had no uveitis, 1 only had symmetric arthritis and multi-joints periarticular hydatoncus. Four children inherited the disease from father. (3) Compared with other 6 non-BS children, BS children had such different clinical characteristic (P < 0.05): All the BS cases had multiple periarticular hydatoncus, which always had no persistent fever, most had no elevated CRP, while non-BS group always had no hydatoncus, most had persistent fever, all had elevated CRP.
CONCLUSIONThe 12 BS children were diagnosed by NOD2 analysis; 7 missense mutations were detected, 3 were novel mutations, adding new findings to human NOD2 mutations. Although classic BS was characterized by skin rash, arthritis, and eye involvement, some presented with less than 3 of the classic features. Chronic symmetric arthritis and multi-joints periarticular hydatoncus were the most comment fetures. Comparing with non-BS group, all BS cases had multi hydatoncus surrounding multi-joints, always had no persistent fever, most had no elevated CRP. Those features may distinguish BS in clinical settings.
Arthritis ; etiology ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Case-Control Studies ; Child ; Child, Preschool ; Cranial Nerve Diseases ; complications ; genetics ; Exanthema ; etiology ; Exons ; genetics ; Female ; Humans ; Infant ; Male ; Mutation ; genetics ; Mutation, Missense ; Nod2 Signaling Adaptor Protein ; genetics ; Synovitis ; complications ; genetics ; Uveitis ; complications ; etiology ; genetics
3.Clinical and Genetic Features of Korean Patients with Recurrent Fever and Multi-System Inflammation without Infectious or Autoimmune Evidence.
Ji Ae YANG ; Ji Yong CHOI ; Eun Ha KANG ; You Jung HA ; Yun Jong LEE ; Yeong Wook SONG
Journal of Korean Medical Science 2016;31(2):196-201
Autoinflammatory disease (AID) is a newly proposed category of disorders characterized by unprovoked episodes of inflammation without any infectious or autoimmune evidence. We aimed to characterize the clinical and genetic features of patients who had recurrent fever and multi-system inflammation but remain unclassified for any established AIDs. Medical records of 1,777 patients who visited our Rheumatology Clinic between March 2009 and December 2010 were reviewed to identify those who met the following criteria; 1) presence of fever, 2) inflammation in two or more organ systems, 3) recurrent nature of fever or inflammation, 4) no evidence of infection or malignancy, 5) absence of high titer autoantibodies, and 6) failure to satisfy any classification criteria for known AIDs. Genotyping was performed for common missense variants in MEFV, NOD2/CARD15, and TNFRSF1A. A small number of patients (17/1,777, 0.95%) were identified to meet the above criteria. Muco-cutaneous and musculoskeletal features were most common, but there was a considerable heterogeneity in symptom combination. Although they did not satisfy any established classification criteria for AIDs, substantial overlap was observed between the clinical spectrum of these patients and known AIDs. According to the newly proposed Eurofever criteria for periodic fevers, eleven of them were classified as TNF receptor-associated periodic syndrome and two as mevalonate kinase deficiency. However, no examined genetic variants including those in TNFRSF1A were found in these patients. A new set of classification criteria needs to be developed and validated for Asian patients with unclassified AIDs.
Adolescent
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Adult
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Cytoskeletal Proteins/genetics
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Female
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Fever/*etiology
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Genotype
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Hereditary Autoinflammatory Diseases/classification/*diagnosis/genetics
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Humans
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Inflammation/*etiology
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Male
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Middle Aged
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Mutation, Missense
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Nod2 Signaling Adaptor Protein/genetics
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Polymorphism, Single Nucleotide
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Receptors, Tumor Necrosis Factor, Type I/genetics
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Recurrence
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Republic of Korea
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Retrospective Studies
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Young Adult
4.Clinical and Genetic Features of Korean Patients with Recurrent Fever and Multi-System Inflammation without Infectious or Autoimmune Evidence.
Ji Ae YANG ; Ji Yong CHOI ; Eun Ha KANG ; You Jung HA ; Yun Jong LEE ; Yeong Wook SONG
Journal of Korean Medical Science 2016;31(2):196-201
Autoinflammatory disease (AID) is a newly proposed category of disorders characterized by unprovoked episodes of inflammation without any infectious or autoimmune evidence. We aimed to characterize the clinical and genetic features of patients who had recurrent fever and multi-system inflammation but remain unclassified for any established AIDs. Medical records of 1,777 patients who visited our Rheumatology Clinic between March 2009 and December 2010 were reviewed to identify those who met the following criteria; 1) presence of fever, 2) inflammation in two or more organ systems, 3) recurrent nature of fever or inflammation, 4) no evidence of infection or malignancy, 5) absence of high titer autoantibodies, and 6) failure to satisfy any classification criteria for known AIDs. Genotyping was performed for common missense variants in MEFV, NOD2/CARD15, and TNFRSF1A. A small number of patients (17/1,777, 0.95%) were identified to meet the above criteria. Muco-cutaneous and musculoskeletal features were most common, but there was a considerable heterogeneity in symptom combination. Although they did not satisfy any established classification criteria for AIDs, substantial overlap was observed between the clinical spectrum of these patients and known AIDs. According to the newly proposed Eurofever criteria for periodic fevers, eleven of them were classified as TNF receptor-associated periodic syndrome and two as mevalonate kinase deficiency. However, no examined genetic variants including those in TNFRSF1A were found in these patients. A new set of classification criteria needs to be developed and validated for Asian patients with unclassified AIDs.
Adolescent
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Adult
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Cytoskeletal Proteins/genetics
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Female
;
Fever/*etiology
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Genotype
;
Hereditary Autoinflammatory Diseases/classification/*diagnosis/genetics
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Humans
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Inflammation/*etiology
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Male
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Middle Aged
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Mutation, Missense
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Nod2 Signaling Adaptor Protein/genetics
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Polymorphism, Single Nucleotide
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Receptors, Tumor Necrosis Factor, Type I/genetics
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Recurrence
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Republic of Korea
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Retrospective Studies
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Young Adult
5.Brazilein inhibits neuronal inflammation induced by cerebral ischemia and oxygen-glucose deprivation through targeting NOD2 expression.
Xiao-Jin YAN ; Yu-Shuang CHAI ; Zhi-Yi YUAN ; Xin-Pei WANG ; Jing-Fei JIANG ; Fan LEI ; Dong-Ming XING ; Li-Jun DU
Chinese Journal of Natural Medicines (English Ed.) 2016;14(5):354-362
Brazilein is reported to have immunosuppressive effect on cardiovascular and cerebral-vascular diseases. The essential roles of innate immunity in cerebral ischemia are increasingly identified, but no studies concerning the influence of brazilein on the innate immunity receptors have been reported. The present study was designed to investigate the regulation of NOD2 (Nucleotide-binding oligomerization domain-containing protein 2) by brazilein for its protection of neuron in cerebral ischemia in vivo and oxygen-glucose deprivation in vitro. The results showed that brazilein could reverse the elevated expression of NOD2 and TNFα (tumor necrosis factor alpha) elicited by cerebral ischemia and reperfusion. This reduction could also be detected in normal mice and C17.2 cells, indicating that this suppressive effect of brazilein was correlated with NOD2. The results from GFP reporter plasmid assay suggested brazilein inhibited NOD2 gene transcription. In conclusion, brazilein could attenuate NOD2 and TNFα expression in cerebral ischemia and NOD2 may be one possible target of brazilein for its immune suppressive effect in neuro-inflammation.
Animals
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Benzopyrans
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administration & dosage
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Brain Ischemia
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drug therapy
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genetics
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immunology
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metabolism
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Cells, Cultured
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Drugs, Chinese Herbal
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administration & dosage
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Glucose
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metabolism
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Humans
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Indenes
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administration & dosage
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Male
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Mice
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Mice, Inbred ICR
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Neurons
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drug effects
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immunology
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Nod2 Signaling Adaptor Protein
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genetics
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metabolism
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Oxygen
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metabolism
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Tumor Necrosis Factor-alpha
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genetics
;
immunology