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Knock-In Mice Limits Responses to Muramyl Dipeptide in Alters Blau Syndrome−Associated Nod2 Mutation Alters Expression of Full-Length NOD2 and Limits Responses to Muramyl Dipeptide in Knock-in Mice This information is current as of September 28, 2021. Jae Dugan, Eric Griffiths, Paige Snow, Holly Rosenzweig, Ellen Lee, Brieanna Brown, Daniel W. Carr, Carlos Rose, James Rosenbaum and Michael P. Davey J Immunol published online 26 November 2014 http://www.jimmunol.org/content/early/2014/11/26/jimmun Downloaded from ol.1402330 Supplementary http://www.jimmunol.org/content/suppl/2014/11/26/jimmunol.140233 http://www.jimmunol.org/ Material 0.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 26, 2014, doi:10.4049/jimmunol.1402330 The Journal of Immunology Blau Syndrome–Associated Nod2 Mutation Alters Expression of Full-Length NOD2 and Limits Responses to Muramyl Dipeptide in Knock-in Mice Jae Dugan,*,† Eric Griffiths,* Paige Snow,* Holly Rosenzweig,*,‡,x Ellen Lee,‡ Brieanna Brown,‡ Daniel W. Carr,*,† Carlos Rose,{ James Rosenbaum,†,‡,‖ and Michael P. Davey*,†,x The biochemical mechanism by which mutations in nucleotide-binding oligomerization domain containing 2 (NOD2) cause Blau syndrome is unknown. Several studies have examined the effect of mutations associated with Blau syndrome in vitro, but none has looked at the implication of the mutations in vivo. To test the hypothesis that mutated NOD2 causes alterations in signaling pathways downstream of NOD2, we created a Nod2 knock-in mouse carrying the most common mutation seen in Blau syndrome, Downloaded from R314Q (corresponding to R334Q in humans). The endogenous regulatory elements of mouse Nod2 were unaltered. R314Q mice showed reduced cytokine production in response to i.p. and intravitreal muramyl dipeptide (MDP). Macrophages from R314Q mice showed reduced NF-kB and IL-6 responses, blunted phosphorylation of MAPKs, and deficient ubiquitination of receptor- interacting protein 2 in response to MDP. R314Q mice expressed a truncated 80-kDa form of NOD2 that was most likely generated by a posttranslational event because there was no evidence for a stop codon or alternative splicing event. Human macrophages from two patients with Blau syndrome also showed a reduction of both cytokine production and phosphorylation of p38 in http://www.jimmunol.org/ response to MDP, indicating that both R314Q mice and cells from patients with Blau syndrome show reduced responses to MDP. These data indicate that the R314Q mutation when studied with the Nod2 endogenous regulatory elements left intact is associated with marked structural and biochemical changes that are significantly different from those observed from studies of the mutation using overexpression, transient transfection systems. The Journal of Immunology, 2015, 194: 000–000. he innate immune system consists of several families containing muramyl dipeptide (MDP) (1, 2). Nod2 is composed of of pattern-recognition receptors capable of recognizing three domains: a C-terminal LRR domain, which is essential for T conserved constituents of microbial pathogens and trig- its MDP-sensing ability; a central nucleotide binding and oligo- by guest on September 28, 2021 gering inflammatory responses. Nucleotide-binding oligomeri- merization domain (NOD), which is important for ATP-dependent zation domain containing 2 (Nod2) is a nucleotide-binding and self-oligomerization; and two N-terminal caspase recruitment leucine-rich repeat (LRR)–containing (NLR) family member that domains that participate in protein–protein interactions and in- recognizes peptidoglycan fragments from bacterial cell walls duction of subsequent intracellular signaling responses (3). After recognition of MDP, Nod2 activates the transcription factors NF- kB and MAPKs via well-characterized pathways leading to in- *Portland Veterans Affairs Medical Center, Portland, OR 97239; †Department of Medicine, Oregon Health and Sciences University, Portland, OR 97239; flammatory responses and release of antimicrobial molecules ‡Department of Ophthalmology, Oregon Health and Sciences University, Portland, (reviewed in Ref. 4). Nod2 plays a pivotal role in host defense in OR 97239; xDepartment of Molecular Microbiology and Immunology, Oregon { the recognition of bacterial pathogens and ssRNA viruses, in- Health and Sciences University, Portland, OR 97239; Division of Rheumatology, DuPont Hospital for Children, Wilmington, DE 19803; and ‖Legacy Devers Eye duction of autophagy, and maintaining homeostasis with com- Institute, Portland, OR 97210 mensal bacteria (reviewed in Ref. 5). Received for publication September 11, 2014. Accepted for publication October 27, The importance of Nod2 in human health is further underscored 2014. by the fact that mutations in NOD2 are associated with the chronic This work was supported by Career Development (5 IK2 BX001295) and Merit inflammatory disorders Crohn’s disease and Blau syndrome (6–8). Review (5 I01 BX000229) Awards from the Department of Veterans Affairs Biomed- ical Laboratory Research and Development Service as well as National Institutes of Given the prevalence of Crohn’s disease and the availability of Health Training Grant 5-T32-AI07472. clinical material for analysis, the role of Nod2 in this disorder has Address correspondence and reprint requests to Dr. Michael P. Davey, Portland been extensively studied. NOD2 mutations linked to Crohn’s dis- Veterans Affairs Medical Center, 3710 SW U.S. Veterans Hospital Road, Mailstop: ease are clustered in the LRR region of the protein, and several Research and Development, Portland, OR 97239-2964. E-mail address: michael. [email protected] hypotheses regarding the mechanism of disease have been exam- The online version of this article contains supplemental material. ined (reviewed in Ref. 9). A current paradigm proposes that loss of Nod2 function, either in controlling the gut microbiome or regu- Abbreviations used in this article: BMDM, bone marrow–derived macrophage; CAPS, cryopyrin-associated periodic syndrome; FRT, FLIPPASE recognition target; KI, knock- lating TLR responses, is the underlying cause of Crohn’s disease. in; KO, knockout; LRR, leucine-rich repeat; MDP, muramyl dipeptide; MS2, tandem The inability of MDP to activate forms of Nod2 carrying Crohn’s mass spectrometry; NLR, nucleotide-binding and leucine-rich repeat–containing; NOD, nucleotide binding and oligomerization domain; NOD2, nucleotide-binding oligomeri- disease–associated mutations has been observed both in vitro using zation domain containing 2; PBDM, peripheral blood–derived macrophage; poly(I:C), cells transiently transfected with mutant forms of Nod2 and in polyinosinic-polycytidylic acid; siRNA, short interfering RNA; TUBE, tandem ubiquitin– macrophages prepared from patients with the disease (2, 10, 11). binding entities; WT, wild-type. In contrast, much less is understood about the mechanism by Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 which mutations in NOD2 cause Blau syndrome, a rare autosomal www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402330 2 BLAU SYNDROME–ASSOCIATED MUTATION AND LOSS OF NOD2 FUNCTION dominant disorder characterized by granulomatous inflammatory every third generation by Southern blot analysis of genomic DNA digested arthritis, dermatitis, and uveitis (12). Mutations associated with with BglII, electrophoresed in 1% agarose, transferred to a nylon membrane Blau syndrome are located in the NOD domain of NOD2, and at (Roche), cross-linked, and then hybridized with a digoxigenin-labeled probe and developed as per the protocol recommended by the manufac- least 17 different mutations have been identified (12, 13). Tran- turer (Roche). The digoxigenin-labeled probe corresponds to a region of sient transfection assays performed in vitro using plasmids with exon 4 in Nod2 (Fig. 1A, top) and was generated by PCR (primer sequence powerful promoters that overexpress NOD2 have found that available upon request). The R314Q locus yields a 3.1-kb restriction frag- mutations associated with Blau syndrome cause excessive NF-kB ment, whereas the WT locus produces a 3.8-kb restriction fragment (Fig. 1B). NOD2-deficient mice (2/2) were purchased from Jackson and MAPK activation compared with the wild-type (WT) form of Laboratory. Mice were maintained under specific pathogen-free conditions NOD2, and this has led to the hypothesis that Blau syndrome is the at the Portland VA Medical Center. All animal studies were performed result of a gain of function of Nod2 (14). However, this gain-of- under protocols approved by the Institutional Animal Care and Use Com- function hypothesis has not been supported when clinical speci- mittee of the Portland VA Medical Center. mens from patients with
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