IFN Priming Is Necessary but Not Sufficient To Turn on a Migratory Dendritic Cell Program in Lupus Monocytes

Rodríguez-Pla, Alicia; Patel, Pinakeen; Maecker, Holden T.; Rosselló-Urgell, José; Baldwin, Nicole; Bennett, Lynda; Cantrell, V. Ashley; Baisch, Jeanine; Punaro, Marilynn; Gotte, Alisa; Nassi, Lorien; Wright, Tracey; Palucka, A. Karolina; Banchereau, Jacques; Pascual, Virginia

doi:10.4049/jimmunol.1301319

Cited by 40 publications

(32 citation statements)

References 69 publications

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“…Remarkably, despite the variability in organ system involvement, inflammatory marker values, autoantibody profile, and SLEDAI scores in the clinically heterogeneous pediatric SLE patients studied (Table 1), the monocyte cytokine signature (MCP1/Mip1β/IL-1RA) was observed in every patient. Consistent with previous literature, we demonstrated that monocytes from SLE patients and healthy controls did no exhibit phenotypic or population frequency differences [63] (Figure 2, Figure S2). …”

Section: Discussionsupporting

confidence: 92%

“…We found that the cytokine signature was induced in CD14 hi monocytes from healthy donors after incubation with SLE patient plasma, but not with age and sex-matched control plasma (Figure 3). While stimulation of healthy donor cells with SLE plasma has been previously demonstrated to induce monocyte apoptosis [67], monocyte differentiation into dendritic cells [63], stimulate IL-10 and IL-6 production by PBMCs [22], and induce transcription of IFN responsive genes [21,68], SLE plasma had not been shown to induce MCP1, Mip1β, and IL-1RA production by healthy CD14 hi monocytes.…”

Section: Discussionmentioning

confidence: 99%

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Mass cytometry identifies a distinct monocyte cytokine signature shared by clinically heterogeneous pediatric SLE patients

O’Gorman

Kong

Balboni

et al. 2017

Journal of Autoimmunity

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Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease with heightened disease severity in children. The incomplete understanding of the precise cellular and molecular events that drive disease activity pose a significant hurdle to the development of targeted therapeutic agents. Here, we performed single-cell phenotypic and functional characterization of pediatric SLE patients and healthy controls blood via mass cytometry. We identified a distinct CD14hi monocyte cytokine signature, with increased levels of monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein-1β (Mip1β), and interleukin-1 receptor antagonist (IL-1RA). This signature was shared by every clinically heterogeneous patient, and reproduced in healthy donors’ blood upon ex-vivo exposure to plasma from clinically active patients only. This SLE-plasma induced signature was abrogated by JAK1/JAK2 selective inhibition. This study demonstrates the utility of mass cytometry to evaluate immune dysregulation in pediatric autoimmunity, by identification of a multi-parametric immune signature that can be further dissected to delineate the events that drive disease pathogenesis.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Mass cytometry identifies a distinct monocyte cytokine signature shared by clinically heterogeneous pediatric SLE patients

O’Gorman

Kong

Balboni

et al. 2017

Journal of Autoimmunity

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“…DCs associated to T-cell and B-cell aggregates are believed to undergo a local maturation process that can perpetuate T cell activation in the lymphocytic aggregates observed in these diseases [124,125]. By contrast, IFN-a priming and LPS stimulation significantly upregulated CCR7 in moDCs from SLE patients [128]. Similarly, immune complexes upregulated CCR7 and increased dermal DC migration in a mouse model of SLE [129].…”

Section: Cdc Recruitmentmentioning

confidence: 99%

Dendritic cell recruitment and activation in autoimmunity

Sozzani

Prete

Bosisio

2017

Journal of Autoimmunity

103

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“…We therefore utilized the well-accepted model of human DC differentiation from peripheral blood monocytes under inflammatory conditions, which is a useful tool to study DC functions ex vivo [14–16]. Pathogenic inflammation can trigger SLE disease exacerbations [17, 18], in which Toll-like receptor 4 (TLR4) and TLR4 responsiveness are important [19]. We therefore choose LPS-activated moDCs as a subtype of DCs generated upon inflammation.…”

Section: Introductionmentioning

confidence: 99%

Elevated expression of miR-142-3p is related to the pro-inflammatory function of monocyte-derived dendritic cells in SLE

et al. 2016

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BackgroundRecent studies have shown that alterations in the function of dendritic cells (DCs) are involved in the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanism of the alteration remains unclear.MethodsWe cultured monocyte-derived DCs (moDCs) in vitro and examined the cytokines and chemokines in the supernatants of moDCs in negative controls (NC) and SLE patients in active phase. We then profiled microRNAs (miRNAs) of LPS-stimulated moDCs in SLE patients and used real-time PCR to verify the differentially expressed miRNAs. A lentiviral construct was used to overexpress the level of miR-142-3p in moDCs of NC. We examined the cytokines and chemokines in the supernatants of moDCs overexpressing miR-142-3p and used Transwell test, flow cytometric analysis and cell proliferation to observe the impact on CD4+ T cells in moDC-CD4+T cell co-culture.ResultsmoDCs in patients with SLE secreted increased level of IL-6, CCL2 and CCL5, with attraction of more CD4+ T cells compared with NC. We found 18 differentially expressed microRNAs in moDCs of SLE patients by microarray, and target gene prediction showed some target genes of differentially expressed miRNAs were involved in cytokine regulation. miR-142-3p was verified among the highly expressed miRNAs in the SLE group and overexpressing miR-142-3p in moDCs of the NC group caused an increase of SLE-related cytokines, such as CCL2, CCL5, CXCL8, IL-6 and TNF-α. Moreover, moDCs overexpressed with miR-142-3p resulted in attraction of an increased number of CD4+ T cells and in suppression of the proportion of Tregs in DC-CD4+T cell co-culture whereas the proliferation of CD4+T cells was not altered.ConclusionsThe results demonstrated a role for miR-142-3p in regulating the pro-inflammatory function of moDCs in the pathogenesis of SLE. These findings suggested that miR-142-3p could serve as a novel therapeutic target for the treatment of SLE.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1158-z) contains supplementary material, which is available to authorized users.

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IFN Priming Is Necessary but Not Sufficient To Turn on a Migratory Dendritic Cell Program in Lupus Monocytes

Cited by 40 publications

References 69 publications

Mass cytometry identifies a distinct monocyte cytokine signature shared by clinically heterogeneous pediatric SLE patients

Mass cytometry identifies a distinct monocyte cytokine signature shared by clinically heterogeneous pediatric SLE patients

Dendritic cell recruitment and activation in autoimmunity

Elevated expression of miR-142-3p is related to the pro-inflammatory function of monocyte-derived dendritic cells in SLE

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