Date: Sunday, October 21, 2018
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Deoxyribonuclease 1-like-3 (DNase1L3) belongs to Deoxyribonuclease 1(DNase1) family. This nuclease originally identified as one of apoptosis- and necrosis-related endonucleases that fragmentates intranucleosomal DNA. Unlike DNase1, DNase1L3 is able to digest protein-associated DNA in addition to naked DNA. Hence, DNase1L3 can degrade nucleosomal DNA more efficiently than DNase1, which is resistant to DNase1 because of the surrounding DNA-binding proteins such as histones. Mutations of DNase1L3 gene that cause loss of function have been reported in murine models of systemic lupus erythematosus (SLE) and familial SLE with an autosomal recessive pattern of inheritance. A recent report showed that DNase1L3-deficient mice also developed features of SLE. In addition, several genetic variants of DNase1L3 are associated with disease susceptibility to systemic sclerosis and hypocomplementemic urticarial vasculitis syndrome. The role of DNase1L3 in human immune systems is largely unknown. We aimed to clarify the expression and function of DNase1L3 in human immune cells.
Methods: We analyzed expression levels of DNase1l3 mRNA in each subset of human peripheral white blood cells, monocyte-derived dendritic cells and monocyte-derived macrophages. The effects of various stimuli on expression levels of DNase1L3 were tested in human immune cells. Nuclease activities of DNase1L3 was examined using various forms of DNA. We also analyzed the effect of secreted DNase1L3 on type 1 interferon production in plasmacytoid dendritic cells (pDCs) mediated by extracellular human DNA. Concentration of DNase1L3 in sera of systemic lupus erythematosus (SLE) patients was also measured.
Results: At steady states, pDCs expressed the highest levels of DNase1l3. In monocyte-derived cells, monocyte-derived dendritic cells (MoDCs) differentiated with interleukin (IL)-4 and granulocyte monocyte colony-stimulating factor (GM-CSF) showed markedly high expression of DNase1L3 mRNA in comparison with MoDCs differentiated with interferon-alpha(IFNα) and GM-CSF. Additionally, IL-4, not IL-13, induced expression of DNase1L3 mRNA in monocytes and monocyte-derived macrophages. As downstream of IL-4 signaling, insulin receptor substrate 2 and extracellular signal-regulated kinase 1/2 were required for the induction of DNase1L3 mRNA expression. DNase1L3 protein was distributed in the cytosol but not in the nucleus and could be secreted into the culture supernatant. The secreted DNase1L3 protein could digest not only naked DNA but also lipid-DNA complexes and protein-DNA complexes, which were only partially digested by DNase1. DNase1L3 could inhibit IFNα secretion from pDCs induced by apoptotic blebs more efficiently than DNase1. We developed enzyme-linked immunosorbent assay of DNase1L3 and identified co-relation between serum DNase1L3 and serum complement 4 in patients with systemic lupus erythematosus.
Conclusion: DNase1L3 is secreted by innate immune cells and may play a critical role in the tissue homeostasis by degrading self-DNA associated with various types of cell death.
To cite this abstract in AMA style:Inokuchi S, Mitoma H, Kawano S, Ayano M, Kimoto Y, Akahoshi M, Arinobu Y, Akashi K, Horiuchi T, Niro H. Deoxyribonuclease 1-like-3 Digests Self-DNA from Dead Cells and Prevents Autoimmunity [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/deoxyribonuclease-1-like-3-digests-self-dna-from-dead-cells-and-prevents-autoimmunity/. Accessed March 18, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/deoxyribonuclease-1-like-3-digests-self-dna-from-dead-cells-and-prevents-autoimmunity/