title: DNA-dependent activator of interferon-regulatory factors (DAI) promotes lupus nephritis by activating the calcium pathway.
abstract: BACKGROUND
  Macrophage M2b polarization conferred by self-DNA immunization initiates and propagates lupus nephritis.
  
  
  RESULTS
  Knockdown of DNA-dependent activator of interferon-regulatory factors (DAI) ameliorates SLE syndrome via blunting macrophage M2b polarization.
  
  
  CONCLUSIONS
  DAI functions as a DNA sensor in self-DNA-induced macrophage M2b polarization and lupus nephritis.
  
  
  CONCLUSIONS
  We disclose the mechanism by which self-DNA induces macrophage M2b polarization and lupus nephritis DNA-dependent activator of interferon-regulatory factors (DAI) functions as a cytoplasmic DNA sensor that activates the innate immune system. We previously found that activated lymphocyte-derived self-apoptotic DNA (ALD-DNA) immunization led to pathological macrophage activation and M2b polarization, which could initiate and propagate murine lupus nephritis. However, the specific DNA sensor(s) as well as underlying molecular mechanisms involved in ALD-DNA-induced macrophage M2b polarization in systemic lupus erythematosus (SLE) disease remains unknown. In this study, we reported that DAI expression was significantly increased in SLE patients as well as in lupus mice. Gain- and loss-of-function studies revealed that DAI was involved in ALD-DNA-induced macrophage activation and M2b polarization. Moreover, ALD-DNA notably induced dimerization/oligomerization of DAI and consequently activation of nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3) signaling pathways via calcium signaling, resulting in macrophage activation and M2b polarization. More importantly, blockade of DAI in vivo or selective knockdown of DAI in macrophages could ameliorate SLE syndrome via blunting macrophage M2b polarization and inhibiting inflammatory response in lupus mice. Our results suggest that DAI could function as a DNA sensor and a regulator in ALD-DNA-induced macrophage M2b polarization and lupus nephritis, providing the possible molecular mechanisms involved in ALD-DNA-induced macrophage M2b polarization in SLE disease and making DAI as a potential therapeutic target for the treatment of SLE.
authors.affiliation: Institute for Immunobiology and Department of Immunology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Yanxing
authors.initials: Y
authors.lastname: Cai
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Gao
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
mesh_terms: D000293:Adolescent; D019264:Adoptive Transfer; D000328:Adult; D000818:Animals; D020013:Calcium Signaling; D016022:Case-Control Studies; D002460:Cell Line; D016764:Cell Polarity; D004247:DNA / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism*; D008181:Lupus Nephritis / Q000276:immunology / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D055503:Protein Multimerization; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C485731:ZBP1 protein, human; D004247:DNA
keywords: Autoimmune Diseases; Calcium; DAI (DLM-1/ZBP1); DNA Sensor; Inflammation; Innate immunity; Lupus Nephritis; Macrophage Polarization; Macrophages; Systemic Lupus Erythematosus (SLE)
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