TY - JOUR
T1 - Cutting edge
T2 - AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II-deficient mice
AU - Baum, Rebecca
AU - Sharma, Shruti
AU - Carpenter, Susan
AU - Li, Quan Zhen
AU - Busto, Patricia
AU - Fitzgerald, Katherine A.
AU - Marshak-Rothstein, Ann
AU - Gravallese, Ellen M.
N1 - Publisher Copyright:
Copyright © 2015 by The American Association of Immunologists, Inc.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84921478452&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84921478452&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1402573
DO - 10.4049/jimmunol.1402573
M3 - Article
C2 - 25548216
AN - SCOPUS:84921478452
SN - 0022-1767
VL - 194
SP - 873
EP - 877
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -