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NLRP12/Monarch-1 Suppression of the NLR Gene Blimp-1/PRDM1

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NLRP12/Monarch-1 Suppression of the NLR Gene Blimp-1/PRDM1 Blimp-1/PRDM1 Mediates Transcriptional Suppression of the NLR Gene NLRP12/Monarch-1 This information is current as Christopher A. Lord, David Savitsky, Raquel Sitcheran, of September 29, 2021. Kathryn Calame, Jo Rae Wright, Jenny Pan-Yun Ting and Kristi L. Williams J Immunol 2009; 182:2948-2958; ; doi: 10.4049/jimmunol.0801692 http://www.jimmunol.org/content/182/5/2948 Downloaded from References This article cites 78 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/182/5/2948.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *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 © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Blimp-1/PRDM1 Mediates Transcriptional Suppression of the NLR Gene NLRP12/Monarch-11 Christopher A. Lord,* David Savitsky,2§ Raquel Sitcheran,‡ Kathryn Calame,§ Jo Rae Wright,* Jenny Pan-Yun Ting,‡ and Kristi L. Williams3*† NLR (nucleotide-binding domain, leucine-rich repeat) proteins are intracellular regulators of host defense and immunity. One NLR gene, NLRP12 (NLR family, pyrin domain containing 12)/Monarch-1, has emerged as an important inhibitor of inflammatory gene expression in human myeloid cells. This is supported by genetic analysis linking the loss of a functional NLRP12 protein to hereditary periodic fever. NLRP12 transcription is diminished by specific TLR stimulation and myeloid cell maturation, consistent with its role as a negative regulator of inflammation. The NLRP12 promoter contains a novel Blimp-1 (B lymphocyte-induced maturation protein-1)/PRDM1 (PR domain-containing 1, with ZNF domain) binding site, and Blimp-1 reduces NLRP12 promoter activity, expression, and histone 3 acetylation. Blimp-1 associates with the endogenous NLRP12 promoter in a TLR-inducible Downloaded from manner and mediates the down-regulation of NLRP12 expression by TLR agonists. As expected, the expression of NLRP12 and Blimp-1 is inversely correlated. Analysis of Blimp-1؊/؊ murine myeloid cells provides physiologic evidence that Blimp-1 reduces NLRP12 gene expression during cell differentiation. This demonstrates a novel role for Blimp-1 in the regulation of an NLR gene. The Journal of Immunology, 2009, 182: 2948–2958. he recognition of microbial components during host in- also known as CATERPILLER, NOD-LRR, NACHT-LRR,or http://www.jimmunol.org/ fection is a key step in activating the innate immune re- NOD-like receptor (5–8). Mutations in several NLR genes have T sponse followed by the induction of inflammatory gene been associated with human disease states, including autoimmu- expression. Pattern-recognition receptors exemplified by TLRs are nity and inflammation. Members of the NLR gene family are in- key regulators in host response to bacterial, viral, and fungal com- volved in regulating cellular activation after exposure to specific or ponents (1, 2). Central to this response is the ability to up-regulate multiple pathogen-derived products (9). NOD2 mediates cellular genes involved in host protection, innate and adaptive immune cell responses to peptidoglycan-derived muramyl dipeptide, leading to recruitment, and pathogen clearance. Although the TLR-mediated activation of inflammatory cytokines and the release of antimicro- inflammatory response is critical for providing immune defense bial peptides from cytosolic granules (10–12). Nlrp1b/Nalp1b reg- by guest on September 29, 2021 against pathogens, dysfunctional responses may lead to both acute ulates disease susceptibility of some murine strains to anthrax le- and chronic inflammatory states manifested as sepsis, inflamma- thal toxin (13). NLRC4/IPAF mediates caspase-1 and IL-1 tion, and autoimmunity (3). Therefore, the intensity and duration processing in response to the flagellin of Salmonella typhimurium of TLR responses must be tightly controlled. and Legionella pneumophila (14–16). Naip5 mediates host sus- In addition to TLR, recent research has focused on the discovery ceptibility to the intracellular pathogen Legionella pneumophila and characterization of a new immune gene family, the NLR (nu- (17). NLRP3/cryopyrin/NALP3 mediates caspase-1 and IL-1 pro- 4 cleotide-binding domain, leucine-rich repeat) gene family (4), cessing in response to an array of stimuli (18–21). The more re- cently described NLRX1 gene negatively regulates the intracellular type I IFN signaling pathway in mitochondria (22). Taken to- Departments of *Cell Biology and †Immunology, Duke University Medical Center, gether, these data suggest that the NLR genes are involved in reg- Durham NC 27710; ‡Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and §Departments of Micro- ulating a variety of host defense processes. biology and Biochemistry & Molecular Biophysics, Columbia University College of The relevance of NLR genes is most apparently revealed by the Physicians and Surgeons, New York, NY 10032 genetic analysis of patients suffering from immune and inflamma- Received for publication May 27, 2008. Accepted for publication December 19, 2008. tory disorders. Mutations in CIITA result in the immunodeficiency The costs of publication of this article were defrayed in part by the payment of page type II bare lymphocyte syndrome (group A) (23). NOD2 muta- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. tions are associated with increased susceptibility to inflammatory 1 This work was supported by National Institutes of Health Grants HL-30923 and Crohn’s disease and to a granulomatous disorder known as Blau HL-084917 (to J.R.W.) and AI057175 and AI063031 (to J.P.T.), as well as a National syndrome (24–26). Hyperactive mutants of the NLRP3 (CIAS1) Research Service Award, University of North Carolina Center for AIDS Research, gene predispose patients to a variety of autoinflammatory disorders Amgen/Federation of Clinical Immunology Societies Fellowship Award, Southeast Regional Center of Excellence for Emerging Infections and Biodefense, and support classified as cryopyrin-associated periodic syndrome, which falls from the American Cancer Society (to K.L.W.). under the general classification of hereditary periodic fever (HPF) 2 Current address: Department of Dermatology, Asahikawa Medical College, Asa- (27–32). Mutations in NLRP1/NALP1 have been genetically linked hikawa, Japan. 3 Address correspondence and reprint requests to Dr. Kristi L. Williams, Department of Cell Biology, Box 3709, Duke University Medical Center, Durham, NC 27710. E-mail address: [email protected] ZNF domain; HKLM, heat-killed Listeria monocytogenes; qPCR, quantitative PCR; 4 Abbreviations used in this paper: NLR, nucleotide-binding domain, leucine-rich DAPA, DNA affinity purification assay; ChIP, chromatin immunoprecipitation; DRB, repeat; HPF, hereditary periodic fever; NLRP12, NLR family, pyrin domain contain- 5,6-dichlororibofuranosyl benzimidazole; GusB, ␤-glucuronidase. ing 12; IRAK, IL-1R-associated kinase; NIK, NF-␬B-inducing kinase; Blimp-1, B lymphocyte-induced maturation protein-1; PRDM1, PR domain-containing 1, with Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.0801692 The Journal of Immunology 2949 with autoimmune disease (33), while NLRP7/NALP7 has been as- data provide a new linkage between Blimp-1 and the innate im- sociated with hydatidiform mole (34). These studies underscore mune TLR and NLR pathways. the contention that NLR family members are important players in both the maintenance of normal immune responses and the onset Materials and Methods of inflammatory disorders. Mice We and others have identified an NLR family member Mon- Ϫ ϩ Prdm1flox/flox and prdm1flox/ mice (48) were crossed with Rosa26ERCre/ arch-1/PYPAF7, recently renamed NLRP12 (NLR family, pyrin mice to generate controls (Rosa26ϩ/ϩprdm1flox/flox) and experimental domain containing 12) (35–37). NLRP12 is expressed primarily by (Rosa26ERCre/ϩprdm1flox/flox) mice. Mice were injected with 1.5 ml of 10 cells of the myeloid-monocytic lineage, including monocytes, mg/ml tamoxifen in sunflower seed oil (0.5 ml/day for 3 days) to induce granulocytes, and eosinophils in humans (36). Although it has gene deletion 3 wk before tissue harvest. Mice were housed in the barrier facility of Columbia University (New York, NY). All experiments were been suggested that some NLR proteins are involved in “sensing” approved by the Institutional Animal Care and Use Committee of Colum- microbial components, currently there is no known ligand for NLR bia University. proteins in general and for NLRP12 specifically. In vitro studies in human cells employing both gene transfection and small hetero- Reagents duplex RNA-mediated
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