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

Abstract

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.

The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells

“…Herein, we also demonstrate that cytokines, previously shown to be increased in the serum or tissue of patients with SLE, strongly enhance the type III IFN production by healthy pDCs. These cytokines include IFN-α [35], GM-CSF [21,36,37], IL-6 [38,39], and IL-3 [40][41][42], but also type III IFN itself [6,43]. Furthermore, all type III IFN subtypes enhanced the IFN-α production.…”

Dimensionality reduction by UMAP reinforces sample heterogeneity analysis in bulk transcriptomic data

“…Datasets with a size of fewer than 100 samples were excluded in order to generate observable and meaningful clusters. The collection covered a diverse range of biomedical research, including the investigations on disease features such as SLE (Banchereau et al, 2016;Davenport et al, 2018;Figgett et al, 2019;Guthridge et al, 2020;Hong et al, 2019;Oon et al, 2019;Toro-Domínguez et al, 2018) and influenza infection (Dunning et al, 2018;Hoang et al, 2014;Zhai et al, 2015), and the evaluation of interventions such as therapies and vaccination (Le-Niculescu et al, 2020;Narang et al, 2018;Rawat et al, 2020;Tasaki et al, 2018;Thakar et al, 2015).…”

Dimensionality reduction by UMAP reinforces sample heterogeneity analysis in bulk transcriptomic data

“…Datasets with the size less than 100 samples were excluded in order to generate observable and meaningful clusters. The collection covered a diverse range of biomedical research including the investigations on disease features such as SLE [23][24][25][26][27][28][29] and influenza infection [30][31][32], and the evaluation on interventions such as therapies and vaccination [33][34][35][36][37].…”