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: Rebecca Baum, Shruti Sharma, Susan Carpenter, Quan-Zhen Li, Patricia Busto, Katherine A Fitzgerald, Ann Marshak-Rothstein, Ellen M Gravallese
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 3 Pg. 873-7 (Feb 01 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25548216 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Aim2 protein, mouse
• Autoantibodies
• Autoantigens
• Cytokines
• DNA-Binding Proteins
• Inflammation Mediators
• Toll-Like Receptors
• Endodeoxyribonucleases
• deoxyribonuclease II

Topics

• Animals
• Antibody Formation (immunology)
• Arthritis, Experimental (diagnosis, genetics, immunology, metabolism)
• Autoantibodies (immunology)
• Autoantigens (genetics, immunology)
• Cluster Analysis
• Cytokines (biosynthesis)
• DNA-Binding Proteins (genetics, metabolism)
• Disease Models, Animal
• Endodeoxyribonucleases (deficiency)
• Female
• Gene Expression Profiling
• Immunity, Innate
• Inflammation Mediators (metabolism)
• Male
• Mice
• Mice, Knockout
• Phenotype
• Signal Transduction
• Toll-Like Receptors (genetics, metabolism)