Background/Purpose: Monocytes play an important role in organ damage, such as in Lupus Nephritis (LN). Although monocytes are typically considered inflammatory cells, evidence shows they also play crucial roles in antigen presentation, homing, wound healing, and fibrosis. The present study aims to identify transcriptomic signatures in circulating monocytes linked to the immune response in active Lupus Nephritis (aLN).

Methods: Circulating monocytes were sorted by FACS from three aLN female patients confirmed by kidney biopsy during initial treatment phase and three female non-SLE Donors (nSD), matched by similar age. After RNA extraction, the transcriptomes were assessed by Next Generation RNA sequencing with Illumina Novaseq platform. Analyses were addressed to identify Differentially Expressed Genes (DEGs). The statistically significant DEGs were compared with an IFN-Regulated gene Signature (IRS) described for interpheronopaties and the resulting set of DEGs were considered as out of the IRS. A list of DEGs from a previous report of SLE-monocyte transcriptional profile was used as a reference of genes highly expressed in our study. The IRS was excluded and the overlapping DEGs between the two studies were assessed. Functional categories and interaction network analysis focusing on immune genes and pathways were addressed to explore the bridging role of the DEGs in circulating monocyte transcriptional profile in the context of aLN.

Results: Monocyte gene expression profiling recognized 176 up-regulated genes differentially expressed in aLN vs nSD. Functional enrichment analysis showed that the most significant functional terms were related to inflammatory response, innate immune response, complement, and coagulation pathways. IRS was present with 23 up-regulated genes. We identified a set of 23 genes out of the IRS list that overlapped with the DEGs previously reported in sorted monocytes from SLE patients. OTOF was the most significant up-regulated gene out of the IRS list. It is a type-I IFN gene related to early anti-inflammatory response and repair and has been reported as a potential marker in SLE flare. Interestingly, the other most significant DEGs were SERPING1 and LGALS3BP and they are not type-I interferon-regulated genes. SERPING1 provides instructions to produce C1 inhibitor. Furthermore, the interaction network analysis for SERPING1 showed that it also has an association with SELP (Selectin P gene), which mediates the interaction between monocytes and neutrophils with activated endothelial cells.  Finally, LGALS3BP, a promising biomarker for lupus nephritis, encodes Galectin-3-binding protein was mainly associated with some proteins involved in cell adhesion such as FN1 (fibronectin), other galectin-binding proteins, and sialic acid-binding Ig-like lectin 10 (SIGLEC10).

Conclusion: Circulating monocytes exhibit a remarkable expression of genes associated with the IFN response in aLN patients. However, not only were type-I IFN-regulated genes in monocytes induced. We also identified different genes involved in pathogenic pathways such as complement activation, cell adhesion, and wound healing, which underlie renal involvement in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/not-only-type-i-interferon-regulated-genes-are-differentially-expressed-in-circulating-monocytes-from-active-lupus-nephritis-patients/