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Homeostatic Milieu Induces Production of Deoxyribonuclease 1–Like 3 from Myeloid Cells

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Homeostatic Milieu Induces Production of Deoxyribonuclease 1–Like 3 from Myeloid Cells Homeostatic Milieu Induces Production of Deoxyribonuclease 1−like 3 from Myeloid Cells This information is current as Shoichiro Inokuchi, Hiroki Mitoma, Shotaro Kawano, Shota of September 25, 2021. Nakano, Masahiro Ayano, Yasutaka Kimoto, Mitsuteru Akahoshi, Yojiro Arinobu, Hiroshi Tsukamoto, Koichi Akashi, Takahiko Horiuchi and Hiroaki Niiro J Immunol published online 18 March 2020 http://www.jimmunol.org/content/early/2020/03/17/jimmun Downloaded from ol.1901304 Supplementary http://www.jimmunol.org/content/suppl/2020/03/17/jimmunol.190130 Material 4.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 18, 2020, doi:10.4049/jimmunol.1901304 The Journal of Immunology Homeostatic Milieu Induces Production of Deoxyribonuclease 1–like 3 from Myeloid Cells Shoichiro Inokuchi,*,† Hiroki Mitoma,* Shotaro Kawano,* Shota Nakano,* Masahiro Ayano,* Yasutaka Kimoto,‡ Mitsuteru Akahoshi,* Yojiro Arinobu,* Hiroshi Tsukamoto,*,x Koichi Akashi,* Takahiko Horiuchi,‡ and Hiroaki Niiro{ DNase 1–like 3 (DNase1L3), which belongs to DNase1 family, was originally identified as one of apoptosis- and necrosis-related endonucleases that fragmentate intranucleosomal DNA. A loss-of-function mutation has been reported in murine models of systemic lupus erythematosus (SLE) and in familial SLE patients. These reports suggest DNase1L3 plays an important role in the prevention of developing SLE; however, expression and function of DNase1L3 in human immune systems have been largely unclarified. As previous reports showed DNase1L3 is expressed in hematopoietic organs, we first analyzed expression levels of DNase1L3 in each subset of human peripheral blood cells by quantitative real-time PCR. Plasmacytoid dendritic cells showed the Downloaded from highest expression levels of DNase1L3 mRNA among peripheral blood cells. IL-4 enhanced DNase1L3 expression in monocytes, monocyte-derived dendritic cells, and monocyte-derived macrophages (MDMs), but not in T cells, B cells, or plasmacytoid dendritic cells. Together with IL-4, all-trans retinoic acid and apoptotic cells efficiently upregulated expression of DNalse1L3 in MDMs. As a result of intracellular signaling analysis, Jak1-IRS2-ERK/PI3K pathway was essential for IL-4–induced DNase1L3 expression. IL-4–treated monocyte-derived dendritic cells and MDMs secreted active DNase1L3 protein that could degrade liposome–DNA complexes, which were resistant to DNase1. Our results indicate DNase1L3 is secreted by innate immune cells http://www.jimmunol.org/ and may play a critical role in the tissue homeostasis and on prevention of developing autoimmunity by degrading self-DNA. The Journal of Immunology, 2020, 204: 000–000. eoxyribonuclease 1–like 3 (DNase1L3) belongs to DNase1 DNase1 because of the surrounding DNA-binding proteins, family (1). This nuclease originally identified as one such as histones. D of apoptosis- (2, 3) and necrosis-related endonucleases Disruption of the nuclease activity has been highlighted in the (4) that fragmentate intranucleosomal DNA (5, 6). Unlike DNase1, context of autoimmunity, notably, systemic lupus erythematosus DNase1L3 has positively charged amino acid sequences in its (SLE). One of the key features of SLE has been thought to be by guest on September 25, 2021 C-terminal region (7), and it is postulated that this feature charac- broken tolerance toward self-component, especially dead cells terizes the function of DNase1L3 to digest protein-associated DNA in (12, 13). The clearance of dead cells is impaired in SLE patients addition to naked DNA (8–11). Therefore, DNase1L3 can degrade from various causes, which leads to an accumulation of auto- nucleosomal DNA more efficiently than DNase1, which is resistant to antigens, followed by autoimmune responses like the emergence of autoreactive lymphocytes and the production of autoanti- bodies. Deletion or loss of function in some DNases was variably associated with the development of autoimmune diseases due to *Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan; †Department of Rheumatol- impaired clearance of dead cells in mice and humans. DNase1- ogy, National Hospital Organization Fukuoka National Hospital, Fukuoka 811-1394, deficient mice develop SLE with classical findings, and poly- Japan; ‡Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu x morphisms of DNase1 were reported in SLE patients (14–16). 874-0838, Japan; Department of Rheumatology, Shin-Kokura Hospital, Kitakyushu 803-8505, Japan; and {Department of Medical Education, Faculty of Medical Sci- DNase2-deficient mice show stimulator of IFN genes (STING)– ences, Kyushu University, Fukuoka 812-8582, Japan dependent type I IFN signature (17, 18), and patients having ORCIDs: 0000-0002-5501-8852 (S.I.); 0000-0002-2107-7459 (H.M.); 0000-0002-5221- loss-of-function mutations in DNASE2 demonstrate severe 1008 (S.K.); 0000-0002-2954-9676 (M. Ayano); 0000-0002-3556-4709 (M. Akahoshi). neonatal anemia, membranoproliferative glomerulonephritis, Received for publication October 29, 2019. Accepted for publication February 12, liver fibrosis, deforming arthropathy, and increased anti-DNA 2020. Abs. Mutation of three prime repair endonuclease (TREX1) was This work was supported by Japan Society for the Promotion of Science KAKENHI reportedtocauseAicardi–Goutie`res syndrome, which manifests Grant JP14535306. STING-dependent type I IFN response and SLE-like symptoms Address correspondence and reprint requests to Dr. Hiroki Mitoma, Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medical (19, 20). Polymorphism of TREX1 was also reported in SLE Sciences, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail address: patients (21). [email protected] As other deoxynucleases, loss of function of DNase1L3 has been The online version of this article contains supplemental material. reported to cause autoimmune phenotypes. Mutations of DNase1L3 Abbreviations used in this article: ATRA, all-trans retinoic acid; DNase1L3, DNase 1–like gene that cause loss of function have been reported in murine models 3; HA, hemagglutinin; IFN-MoDC, MoDC differentiated by type 1 IFN and GM-CSF; IL-4–MoDC, MoDC differentiated by IL-4 and GM-CSF; IRS2, insulin receptor of SLE (22). Familial SLE is caused by DNase1L3 mutations with substrate 2; MDM, monocyte-derived macrophage; MoDC, monocyte-derived den- an autosomal recessive pattern of inheritance in a very-high dritic cell; NET, neutrophil extracellular trap; pDC, plasmacytoid dendritic cell; qPCR, penetrance rate, which onset in childhood and show the typical quantitative PCR; shRNA, short hairpin RNA; SLE, systemic lupus erythematosus. phenotype of SLE, such as elevation of anti-dsDNA Abs, low Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 serum complement, and lupus nephritis (23). In addition, a recent www.jimmunol.org/cgi/doi/10.4049/jimmunol.1901304 2 HOMEOSTASIS-ASSOCIATED MYELOID CELLS PRODUCE DNase1L3 report showed that DNase1L3-deficient mice also develop features medium was replaced by fresh medium with or without 20 ng/ml human of SLE (24). These mice presented impaired processing of the IL-4. After 24 h, indicated analyses were performed. chromatin in microparticles from apoptotic cells, and the authors Differentiation of human monocyte-derived cells suggested a deficiency of DNase1L3 led to a loss of self-tolerance toward apoptotic cells and contribute to SLE pathogenesis. RPMI 1640 supplemented with 10% FBS (Sigma-Aldrich), MEM Non- Essential Amino Acids Solution (FUJIFILM Wako Pure Chemical), Moreover, several genetic variants of DNase1L3, which have 50 nM of 2-ME (Sigma-Aldrich), and Penicillin-Streptomycin Solution less nuclease activity than wild type, were also associated with (FUJIFILM Wako Pure Chemical) were used for primary cell culture. disease susceptibility in systemic sclerosis (25–27), rheumatoid Monocytes were isolated from healthy subjects using RosetteSep Human arthritis (28), and hypocomplementemic urticarial vasculitis Monocyte Enrichment Cocktail (STEMCELL Technologies). For differ- entiation of monocyte-derived dendritic cells (MoDCs), 2.5 3 105 of syndrome (29). monocytes in 500 ml of medium with GM-CSF (20 ng/ml; PeproTech) and Accumulating evidences indicate that DNase1L3 plays an es- IL-4 (20 ng/ml; PeproTech) were seeded into 48-well tissue culture plates. sential role in processing self-DNA and is required for preventing Culture medium was changed every 3 d. After 5 d of differentiation, the development of autoimmunity. DNase1L3-deficient mice and indicated experiments
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