A Novel Type I IFN-Producing Cell Subset in Murine Lupus

Lee, Pui Y.; Weinstein, Jason S.; Nacionales, Dina C.; Scumpia, Philip O.; Li, Yi; Butfiloski, Edward J.; Rooijen, Nico van; Moldawer, Lyle L.; Satoh, Minoru; Reeves, Westley H.

doi:10.4049/jimmunol.180.7.5101

Cited by 110 publications

(160 citation statements)

References 36 publications

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“…This observation is congruent with the finding that lymphoid tissue from TMPD-induced granulomas contains activated dendritic cells, 30 as well as Ly6C high monocytes, 31 both of which produce type I interferon which in turn would induce Ifi genes. In DBA mesenteries, both Ifi202 and, to a lesser extent, Ifi204/Ifi205, levels increased by day 18; it is possible that the enhanced expression of these genes compensates for the absence of Mndal and low levels of Ifi203 seen in DBA.…”

Section: Discussionsupporting

confidence: 88%

Mndal, a new interferon-inducible family member, is highly polymorphic, suppresses cell growth, and may modify plasmacytoma susceptibility

Zhang

Kagan

Dubois

et al. 2009

Blood

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The human HIN-200 gene cluster and its mouse counterpart, the interferon inducible-200 (Ifi200) family, both on Chr 1, are associated with several diseases, including solid tumors and lupus. Our study was initiated to identify the modifier gene(s) encoded by the Pctm locus, in which mouse B-cell plasmacytomas induced by pristane are associated with heterozygosity of Chr 1 genes near the Ifi200 cluster. A screen for differentially expressed genes in granulomatous tissues induced by pristane in resistant and susceptible strains identified a new Ifi200 member whose expression was 1000-fold higher in the strain carrying the resistant allele of Pctm and was the most highly expressed Ifi200 gene. The gene, designated Mndal (for MNDA-like, myeloid nuclear differentiation antigen-like), was absent in the susceptible genome, as were genomic sequences upstream of Ifi203, the gene adjacent to Mndal. Ectopic expression of MNDAL suppressed cell growth, which, together with the disease susceptibility of heterozygotes at the Pctm locus, suggests that Mndal, perhaps with Ifi203, acts as a tumor suppressor and display(s) haploinsufficiency. Mndal is highly polymorphic among inbred mouse strains, because it is absent in 10 of 24 strains. This polymorphism may have implications for other disease modifiers mapping to the same region.

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Section: Discussionsupporting

confidence: 88%

Mndal, a new interferon-inducible family member, is highly polymorphic, suppresses cell growth, and may modify plasmacytoma susceptibility

Zhang

Kagan

Dubois

et al. 2009

Blood

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“…The production of type I IFN seems integral to the pathogenesis of SLE (27,31), and IRF7 mediates the gene induction by IFNs (21). We thus studied whether the expression of ISGs (the IFN signature) is modulated in TMPD-induced Irf7 2/2 mice.…”

Section: No Impairment Of Tmpd-induced Apoptosis In Irf7 2/2 Micementioning

confidence: 99%

“…We thus studied whether the expression of ISGs (the IFN signature) is modulated in TMPD-induced Irf7 2/2 mice. In this model, upregulation of IFN-a, IFN-b, and ISGs precedes (within 2 wk after the peritoneal TMPD challenge) the appearance of lupus autoantibodies and of signs of glomerulonephritis (∼4-6 mo after challenge) following the TMPD induction (22,27,31). Hence, real-time PCR analysis of ISGs was conducted 2 wk after TMPD treatment.…”

Section: No Impairment Of Tmpd-induced Apoptosis In Irf7 2/2 Micementioning

confidence: 99%

Essential Requirement for IFN Regulatory Factor 7 in Autoantibody Production but Not Development of Nephritis in Murine Lupus

Miyagawa

Tagaya

Ozato

et al. 2016

The Journal of Immunology

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Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the production of autoantibodies against nuclear components. Recent genetic studies of SLE patients have revealed that IFN regulatory factor (IRF) 7 gene polymorphisms are associated with an increased risk of SLE, but the precise role of IRF7 in SLE development is not fully understood. We investigated the role of IRF7 in the pathogenesis of SLE using a mouse model and saw a curious dissociation of autoantibody production and development of glomerulonephritis. SLE was chemically induced into IRF7-deficient mice, and glomerulonephritis with deposits of IgG and lipogranulomas were observed after 10 mo. However, these mice failed to produce anti-dsDNA, ssDNA, ribonucleoprotein, and Sm autoantibodies. Following the chemical induction, IRF7-deficient mice expressed substantially lower levels of IFN-stimulated genes than did wild-type mice, but NF-κB target genes were equally upregulated in both strains. Therefore, the type I IFN pathway seems critical for the autoantibody production, but the NF-κB activation is sufficient for the development of glomerulonephritis in this model. Our study thus demonstrates a specific requirement for IRF7 in autoantibody production and uncovers a new layer of complexity in the pathogenesis of SLE.

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“…After the final extension (72°C for 10 minutes), a melting curve analysis was performed to ensure specificity of the products. Primers used in this study have been described, 18,19 except for the following: CCL7 (forward 5Ј-GATCTCTGC-CACGCTTCTGT-3Ј and reverse 5Ј-ATAGCCTCCTCGAC-CCACTT-3Ј); CCL12 (forward 5Ј-GTCCTCAGGTATTGGCT-GGA-3Ј and reverse 5Ј-CACTGGCTGCTTGTGATTCT-3Ј); CX3CL1 (forward 5Ј-CGCGTTCTTCCATTTGTGTA-3Ј and reverse 5Ј-AGCTGATAGCGGATGAGCAA-3Ј); CXCL1 (forward 5Ј-GCTGGGATTCACCTCAAGAA-3Ј and reverse 5Ј-TCTCCGTTACTTGGGGACAC-3Ј); arginase-1 (forward 5Ј-GCACTGAGGAAAGCTGGTCT-3Ј and reverse 5Ј-GACC-GTGGGTTCTTCACAAT-3Ј); TGF-␤ (forward 5Ј-AGCCCG-AAGCGGACTACTAT-3Ј and reverse 5Ј-TTCCACATGTT-GCTCCACAC-3Ј) cathepsin S (forward 5Ј-ACCTACCAAGT-GGGCATGAA-3Ј and reverse 5Ј-TGTCAGGCAATGTC-CGATTA); cathepsin L (forward 5Ј-CCATCCGTCTCTCC-AGTTCT-3Ј and reverse 5Ј-ATAGCCATAGCCCACCAACA-3Ј); MMP-2 (forward 5Ј-CAGAACACCATCGAGACCAT-3Ј and reverse 5Ј-CCAGGTCAGGTGTGTAACCA-3Ј); and MMP-9 (forward 5Ј-CATGCACTGGGCTTAGATCA-3Ј and reverse 5Ј-GGCTTAGAGCCACGACCATA-3Ј).…”

Section: Quantitative Real-time Pcr (Q-pcr)mentioning

confidence: 99%

Type I Interferon Modulates Monocyte Recruitment and Maturation in Chronic Inflammation

Lee

Kumagai

et al. 2009

The American Journal of Pathology

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172

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Chronic inflammation is characterized by continuous recruitment and activation of immune cells such as monocytes in response to a persistent stimulus. Production of proinflammatory mediators by monocytes leads to tissue damage and perpetuates the inflammatory response. However, the mechanism(s) responsible for the sustained influx of monocytes in chronic inflammation are not well defined. In chronic peritonitis induced by pristane, the persistent recruitment of Ly6C hi inflammatory monocytes into the peritoneum was abolished in type I interferon (IFN-I) receptor-deficient mice but was unaffected by the absence of IFN-␥, tumor necrosis factor-␣, interleukin-6, or interleukin-1. IFN-I signaling stimulated the production of chemokines (CCL2, CCL7, and CCL12) that recruited Ly6C hi monocytes via interactions with the chemokine receptor CCR2. Interestingly, after 2,6,10,14-tetramethylpentadecane treatment, the rapid turnover of inflammatory monocytes in the inflamed peritoneum was associated with a lack of differentiation into Ly6C lo monocytes/macrophages, a more mature subset with enhanced phagocytic capacity. In contrast, Ly6C hi monocytes differentiated normally into Ly6C lo cells in IFN-I receptor-deficient mice. The effects of IFN-I were specific for monocytes as granulocyte migration was unaffected in the absence of IFN-I signaling. Taken together, our findings reveal a novel role of IFN-I in promoting the recruitment of inflammatory monocytes via the chemokine receptor CCR2. Continuous monocyte recruitment and the lack of terminal differentiation induced by IFN-I may help sustain the chronic inflammatory response.

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A Novel Type I IFN-Producing Cell Subset in Murine Lupus

Cited by 110 publications

References 36 publications

Mndal, a new interferon-inducible family member, is highly polymorphic, suppresses cell growth, and may modify plasmacytoma susceptibility

Mndal, a new interferon-inducible family member, is highly polymorphic, suppresses cell growth, and may modify plasmacytoma susceptibility

Essential Requirement for IFN Regulatory Factor 7 in Autoantibody Production but Not Development of Nephritis in Murine Lupus

Type I Interferon Modulates Monocyte Recruitment and Maturation in Chronic Inflammation

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