title: Cutting edge: AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II-deficient mice.
abstract: Innate immune pattern recognition receptors sense nucleic acids from microbes and orchestrate cytokine production to resolve infection. Inappropriate recognition of host nucleic acids also results in autoimmune disease. In this study, we use a model of inflammation resulting from accrual of self DNA (DNase II(-/-) type I IFN receptor [Ifnar](-/-)) to understand the role of pattern recognition receptor-sensing pathways in arthritis and autoantibody production. Using triple knockout (TKO) mice deficient in DNase II/IFNaR together with deficiency in either stimulator of IFN genes (STING) or absent in melanoma 2 (AIM2), we reveal central roles for the STING and AIM2 pathways in arthritis. AIM2 TKO mice show limited inflammasome activation and, similar to STING TKO mice, have reduced inflammation in joints. Surprisingly, autoantibody production is maintained in AIM2 and STING TKO mice, whereas DNase II(-/-) Ifnar(-/-) mice also deficient in Unc93b, a chaperone required for TLR7/9 endosomal localization, fail to produce autoantibodies to nucleic acids. Collectively, these data support distinct roles for cytosolic and endosomal nucleic acid-sensing pathways in disease manifestations.
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Baum
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Diabetes Center, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143;
authors.forename: Susan
authors.initials: S
authors.lastname: Carpenter
authors.affiliation: Microarray Core Facility, Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75235; and.
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Patricia
authors.initials: P
authors.lastname: Busto
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; Ellen.Gravallese@umassmed.edu.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Gravallese
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D001169:Arthritis, Experimental / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D016000:Cluster Analysis; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004706:Endodeoxyribonucleases / Q000172:deficiency*; D005260:Female; D020869:Gene Expression Profiling; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics* / Q000378:metabolism
chemical_list: C540422:Aim2 protein, mouse; D001323:Autoantibodies; D001324:Autoantigens; D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D051193:Toll-Like Receptors; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II