SLE Peripheral Blood B Cell, T Cell and Myeloid Cell Transcriptomes Display Unique Profiles and Each Subset Contributes to the Interferon Signature

Becker, Amy M.; Dao, Kathryn H.; Han, Bobby Kwanghoon; Kornu, Roger; Lakhanpal, Shuchi; Mobley, Angela B.; Li, Quan Zhen; Lian, Yun; Wu, Tianfu; Reimold, Andreas M.; Olsen, Nancy J.; Karp, David R.; Chowdhury, Fatema Z.; Farrar, J. David; Satterthwaite, Anne B.; Mohan, Chandra; Lipsky, Peter E.; Wakeland, Edward K.; Davis, Laurie S.

doi:10.1371/journal.pone.0067003

Cited by 167 publications

(146 citation statements)

References 77 publications

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“…It was shown that B cells display a significant IFN-I inducible gene signature in SLE patients [19]. Consistently, we also observed higher IFIT1, IFIT2, MX1, OAS1, USP18, and IFI44 expression levels, which are downstream genes of the JAK1-STAT1 signaling cascade (Supporting Information Fig.…”

Section: Sts-1 Promotes Ifn-α-induced Autophagy Through Jak1-stat1 Sisupporting

confidence: 88%

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STS‐1 promotes IFN‐α induced autophagy by activating the JAK1‐STAT1 signaling pathway in B cells

et al. 2015

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Systemic lupus erythematosus (SLE) is Keywords: Autophagy B cells Interferon-α STS-1 Systemic lupus erythematosusAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacroautophagy, conventionally referred to as autophagy, is a highly conserved lysosome-mediated catabolic process in which cytoplasmic contents are degraded and recycled [1]. Recently, various autophagic functions have been recognized in innate and adaptive immunity, including pathogen clearance, inflammasome regulation, and maintenance of tolerance [2,3]. The observations Correspondence: Dr. Yayi Hou e-mail: yayihou@nju.edu.cn of the autophagic functions that trigger or exacerbate autoimmunity show that autophagy participates in the pathogenesis of autoimmune disorders, such as systemic lupus erythematosus (SLE) [4][5][6].SLE is a potentially fatal autoimmune disease that is characterized by B-cell hyperactivation and production of autoantibodies that mainly target nuclear components [7]. Of note, B cells play a central role in the pathogenesis of SLE through the production of pathogenic autoantibodies [8,9]. Enhanced autophagic activities have been observed in B cells from SLE patients and NZB/W F1 mice [5]. Studies have increasingly demonstrated that autophagy C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2378 Guanjun Dong et al. Eur. J. Immunol. 2015. 45: 2377-2388 is involved in B-cell development, homeostasis, activation, and antibody response [10,11]. Because B cells are a major player in SLE, autophagy-mediated modulation of B cells can directly influence the pathophysiology of SLE. In fact, the contribution of autophagy to the pathogenesis of SLE has been supported by the beneficial effects of autophagy modulating molecules on disease development in SLE patients and lupus-prone mice, such as rapamycin and P140 peptide [12,13]. Given that the autophagy pathway can be considered as an effective therapeutic target in the treatment of SLE, the exploration of the enhanced autophagic activity mechanism of B cells during SLE is urgently needed. Autophagy can be provoked by host-derived cytokines, IFN-I/II or pattern recognition receptors in many cell types [2,14,15]. However, to date, the enhanced autophagic activity mechanism in SLE B cells remains unknown, although BCR ligands have been shown to induce autophagy in B cells [16,17]. Of note, IFN-α, a central cytokine in the pathogenesis of SLE, can induce and accelerate SLE symptoms in patients and mice [18]. Importantly, B cells display a significant IFN-I inducible gene signature in SLE patients [19] and IFN-α impacts B-cell functions through a variety of mechanisms, such as TLR7 expression, differentiation, and class-switch recombination [20][21][22]. Importantly, IFN-α provokes autophagy in many different cell types and JAK1-STAT1 signaling plays an absolutely necessary role in this process [23]. However, it remains unknown whether IFN-α can induce autophagy in primary human and murine B cells.ST...

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Section: Sts-1 Promotes Ifn-α-induced Autophagy Through Jak1-stat1 Sisupporting

confidence: 88%

“…As is known, the TLR7, TLR9, BCR, and IFN-α pathways are aberrantly activated in SLE B cells [19,30,31]. To identify the molecular events leading to STS-1 overexpression, we evaluated the effects of the TLR7, TLR9, BCR, and IFN-α pathways on STS-1 expression regulation in B cells.…”

Section: The Tlr7 Tlr9 and Bcr Pathways Upregulate Sts-1 Expressionmentioning

confidence: 99%

STS‐1 promotes IFN‐α induced autophagy by activating the JAK1‐STAT1 signaling pathway in B cells

et al. 2015

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“…Several gene expression studies have contributed to the discovery of genes related to SLE, especially those studies focused on gene transcripts in T cells and B cells. 33,40,41 In this study, we found that most DEGs were enriched in cell cycle pathways in SLE B cells. In accordance with our analysis, the publicly available datasets for the SLE transcriptome also revealed that significant pathways of overexpressed genes are related to the cell cycle.…”

Section: Discussionmentioning

confidence: 53%

Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus

et al. 2015

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Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B-cell hyperreactivity. The Toll-like receptor 7 (TLR7) signaling pathway is abnormally activated in SLE B cells. CyclinD3 (CCND3) plays an important role in B-cell proliferation, development, and differentiation. Although previous studies focused on the B cell-intrinsic role of TLR7 for the development of spontaneous germinal centers, the influence of TLR7 on CCND3 in SLE B cells is still not clear. Here, we used a B-cell profiling chip and found that CCND3 was related to SLE and significantly elevated in SLE B cells. Moreover, we determined that the expression level of CCND3 was higher, while miR-15b was significantly lower in the B cells from SLE patients and B6.MRL-Faslpr/J lupus mice compared to normal subjects. Furthermore, we demonstrated that the activation of TLR7 dramatically increased CCND3 expression but significantly decreased miR-15b in B cells in vitro and we identified that CCND3 is a direct target of miR-15b. To further confirm our results, we established another lupus model by topically treating C57BL/6 (B6) mice with the TLR-7 agonist imiquimod (IMQ) for 8 weeks according to the previously described protocol. Expectedly, topical treatment with IMQ also significantly increased CCND3 and decreased miR-15b in B cells of B6 mice. Taken together, our results identified that the activation of TLR7 increased CCND3 expression via the downregulation of miR-15b in B cells; thus, these findings suggest that extrinsic factor-induced CCND3 expression may contribute to the abnormality of B cell in SLE. Cellular & Molecular Immunology

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“…It will be interesting to investigate whether other chronic innate immune activation mouse models present similar metabolic phenotypes. Nonetheless, because metabolic dysregulation is becoming more commonly observed in autoimmune diseases such as SLE, which is often associated with elevated type I IFN gene signature and chronic activation of TBK1-dependent innate immune pathways (21,25,26). The molecular mechanism we delineated here with the Trex1 −/− mouse model highlight TBK1 as a potentially useful therapeutic target that mediates the crosstalk between immune response and metabolism.…”

Section: Chronic Inflammation Dysregulated Metabolismmentioning

confidence: 83%

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

Hašan

Gonugunta

Dobbs

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Three-prime repair exonuclease 1 knockout (Trex1 −/− ) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANKbinding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1 −/− mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1 −/− background, and many metabolic defects persist in Trex1 −/− Irf3 −/− cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1 −/− mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1 −/− cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.M ammals have evolved complex and integrated systems of immunity and metabolism to maintain and defend internal and environmental threats. Increasing numbers of immune regulators have been found to play critical roles in metabolism. Studies from recent years have established an integrated view on the shared architecture between adaptive immunity and metabolism, including how they correspond to stimulus in disease settings. However, cell-intrinsic innate immune regulation of metabolic pathways remains poorly understood. This is in part due to the fact that overwhelming systemic inflammation in chronic diseases often masks direct underlying molecular causes.We have previously characterized an autoimmune/autoinflammatory disease mouse model, three-prime repair exonuclease 1 knockout (Trex1 −/− ) (1). TREX1, also known as DNase III, is an exonuclease that localizes to the endoplasmic reticulum (ER) to prevent aberrant accumulation of self-DNA or glycans that would trigger immune activation (2, 3). Mutations of the TREX1 gene have been associated with several autoinflammatory and autoimmune diseases, including Aicardi-Goutières syndrome and systemic lupus erythematosus (SLE) (4). Trex1 −/− mice suffer from systemic inflammation caused largely by chronic activation of the cytosolic DNA sensing pathway through the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) cascade (5-7). We showed previously that TREX1 also regulates lysosomal biogenesis through the mTORC1-TFEB pathway and that Trex1 −/− mouse embryonic fibroblasts (MEFs) exhibit drastically reduced mTORC1 activity compare...

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SLE Peripheral Blood B Cell, T Cell and Myeloid Cell Transcriptomes Display Unique Profiles and Each Subset Contributes to the Interferon Signature

Cited by 167 publications

References 77 publications

STS‐1 promotes IFN‐α induced autophagy by activating the JAK1‐STAT1 signaling pathway in B cells

STS‐1 promotes IFN‐α induced autophagy by activating the JAK1‐STAT1 signaling pathway in B cells

Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

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