IL-3 contributes to development of lupus nephritis in MRL/Ipr mice

Renner, Karl; Hermann, Fabian; Schmidbauer, Kathrin; Talke, Yvonne; Gómez, Manuel R.; Schiechl, Gabriela; Schlossmann, Jens; Brühl, Hilke; Anders, Hans‐Joachim; Mack, Matthias

doi:10.1038/ki.2015.196

Cited by 42 publications

(36 citation statements)

References 59 publications

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“…Moreover, i.p. injection of IL-3 may also induce peripheral activation of leukocytes, thus facilitating their transendothelial migration, and could increase the survival of T and B cells, as shown previously in mice with lupus nephritis (23). Interestingly, injection of IL-3 mainly increased in the infiltration of CD4 + and CD8 + T cells, indicating that migration of T cells into the CNS is, to a large degree, dependent on the presence of IL-3, while migration of monocytes into the CNS is less dependent on IL-3.…”

Section: Discussionsupporting

confidence: 55%

“…IL-3 induces activation and/or increases the survival of various target cells, including mast cells, basophils, monocytes, DCs, B cells, T cells, and endothelial cells (14)(15)(16)(17)(18)(19)(20)(21). An important role of IL-3 in inflammation and autoimmunity was recently shown in a model of sepsis (9), as well as in models of arthritis and lupus nephritis (22,23). IL-3 increases the release of monocytes and neutrophils from the BM, activates monocytes and BM cells to release proinflammatory cytokines, has antiapoptotic effects on various leukocytes, and activates endothelial cells to upregulate E-and P-selectin (9,(14)(15)(16)(17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

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IL-3 promotes the development of experimental autoimmune encephalitis

Renner¹,

Hellerbrand²,

Hermann³

et al. 2016

JCI Insight

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Little is known about the role of IL-3 in multiple sclerosis (MS) in humans and in experimental autoimmune encephalomyelitis (EAE). Using myelin oligodendrocyte glycoprotein (MOG) peptide-induced EAE, we show that CD4 T cells are the main source of IL-3 and that cerebral IL-3 expression correlates with the influx of T cells into the brain. Blockade of IL-3 with monoclonal antibodies, analysis of IL-3 deficient mice, and adoptive transfer of leukocytes demonstrate that IL-3 plays an important role for development of clinical symptoms of EAE, for migration of leukocytes into the brain, and for cerebral expression of adhesion molecules and chemokines. In contrast, injection of recombinant IL-3 exacerbates EAE symptoms and cerebral inflammation. In patients with relapsing-remitting MS (RRMS), IL-3 expression by T cells is markedly upregulated during episodes of relapse. Our data indicate that IL-3 plays an important role in EAE and may represent a new target for treatment of MS.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

IL-3 promotes the development of experimental autoimmune encephalitis

Renner¹,

Hellerbrand²,

Hermann³

et al. 2016

JCI Insight

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“…We find that the IL-3 and Wnt signatures emerge as the most discriminating between SLE and control donors ( Supplementary Figure 2e). Notably, previous studies support a role for IL-3 in SLE in connection with B cells: IL-3 is a growth factor for B cells [36], serum levels of IL-3 have been observed to be increased in SLE patients vs healthy controls [37], and a recent study in a lupus nephritis mouse model found that IL-3 blockade ameliorated disease symptoms and notably reduced splenic B-cell counts [38].…”

Section: Distinct Signature Modules Drive Transcriptional Variation Imentioning

confidence: 90%

Functional Interpretation of Single-Cell Similarity Maps

DeTomaso

Jones

Subramaniam

et al. 2018

Preprint

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We present VISION, a tool for annotating the sources of variation in single cell RNA-seq data in an automated, unbiased and scalable manner. VISION operates directly on the manifold of cell-cell similarity and employs a flexible annotation approach that can operate either with or without preconceived stratification of the cells into groups or along a continuum. We demonstrate the utility of VISION using a relatively homogeneous set of B cells from a cohort of lupus patients and healthy controls and show that it can derive important sources of cellular variation and link them to clinical phenotypes in a stratification free manner. VISION produces an interactive, low latency and feature rich web-based report that can be easily shared amongst researchers. BackgroundRecent technological advancements have allowed transcriptional profiling at the single-cell level [1,2,3]. This has enabled a deeper investigation into cellular heterogeneity [4], the identification of new cellular subtypes [5,6], and more detailed modeling of developmental processes [7,8]. Notably, the data produced in a single-cell RNA-seq (scRNA-seq) experiment is distinct from that of bulk RNA-seq in that it is typically sparse (with many expressed genes remaining undetected), and consists of a very high number of data points [9]. Furthermore, while bulk studies are usually conducted in a comparative setting (e.g., case control studies), most investigations of scRNAseq are based on comparisons of cells within a sample, without any preconceived labels of these cells.A typical primary step in the analysis of scRNA-seq data is therefore to extract a meaningful labeling by partitioning the cells into groups [10,11] or by placing the cells along some contin- *

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“…In the MRL/lpr murine lupus model, IL-3 administration exacerbated nephritis, and IL-3 blockade alleviated disease and decreased autoantibody production. 2 Plasma levels of IL-3 increased during disease progression in these mice, and IL-3 was produced by CD4 + T cells derived from the spleen and bone marrow, and by CD8 + T cells derived from the spleen. Recently, a therapeutic monoclonal antibody that neutralises IL-3 and also depletes CD123 + cells was shown to decrease cell types (plasmacytoid dendritic cells [pDCs] and basophils) and cytokines implicated in the pathogenesis of SLE, including type I and III IFNs, in primary cells from SLE patients.…”

Section: Introductionmentioning

confidence: 87%

“…Recent studies of murine lupus have more directly identified a role for IL‐3. In the MRL/ lpr murine lupus model, IL‐3 administration exacerbated nephritis, and IL‐3 blockade alleviated disease and decreased autoantibody production . Plasma levels of IL‐3 increased during disease progression in these mice, and IL‐3 was produced by CD4 + T cells derived from the spleen and bone marrow, and by CD8 + T cells derived from the spleen.…”

Section: Introductionmentioning

confidence: 98%

A potential association between IL‐3 and type I and III interferons in systemic lupus erythematosus

Oon

Monaghan

et al. 2019

Clin & Trans Imm

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ObjectivesPlasmacytoid dendritic cells (pDCs), through the production of type 1 interferons (IFNs) and other cytokines, are major contributors to systemic lupus erythematosus (SLE) pathogenesis. IL‐3 promotes pDC survival, but its role in SLE is not well characterised. This study investigated serum IL‐3 and IFN levels, and a whole blood ‘IL‐3 gene signature’, in human SLE.MethodsSerum cytokine levels were measured by ELISA in n = 42 SLE patients, and n = 44 healthy donors. IL‐3‐regulated genes were determined by RNASeq of healthy donor whole blood cells (WBCs) stimulated in vitro with IL‐3 for 6 or 24 h. Whole blood cell RNASeq analysis was undertaken in a separate cohort of n = 31 SLE patients, and n = 28 healthy donors.ResultsSerum IL‐3 levels correlated with IFNα (r = 0.612, 95% CI 0.455–0.733, P < 0.001) and type III IFN (r = 0.585, 95% CI 0.406–0.720, P < 0.0001). IL‐3 stimulation of WBC in vitro altered 794 genes (−1 ≥ logFC ≥ 1, FDR < 0.05), of which 35 overlapped with genes differentially expressed between SLE and healthy donors. These 35 genes were expressed in 27/31 SLE donors, revealing the presence of an ‘IL‐3 gene signature’. There was strong correlation between the IL‐3 signature and an IFN signature, as determined by hierarchical clustering of the 500 most variable genes in SLE donors (r = 0.939, 95% CI 0.898–0.964, P < 0.0001).ConclusionA dual IL‐3/IFN gene signature is a feature of SLE. An association between IL‐3 and IFN raises the possibility that dual blockade of IL‐3 and IFN may be especially useful for SLE patients with this dual cytokine gene signature.

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IL-3 contributes to development of lupus nephritis in MRL/Ipr mice

Cited by 42 publications

References 59 publications

IL-3 promotes the development of experimental autoimmune encephalitis

IL-3 promotes the development of experimental autoimmune encephalitis

Functional Interpretation of Single-Cell Similarity Maps

A potential association between IL‐3 and type I and III interferons in systemic lupus erythematosus

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