Background/Purpose: The present study aimed at: 1- Identifying altered SLE monocytes transcriptomic signatures linked to the immune response and its association with clinical features. 2- Evaluating the involvement of those altered molecular profiles in lupus nephropathy. 3- Analyzing mechanistically the impact of spliceosome alterations in the SLE-monocytes activity.

Methods: Sixty SLE patients and forty healthy donors (HD) were included in the study. Infiltration rate of myeloid cells was analyzed in kidney biopsies by Immunohistochemistry. Circulating monocytes were purified from peripheral blood by immune-magnetic selection and both, transcriptome and spliceosome profiling were assessed, respectively, by Nanostring and a microfluidic qPCR array (Fluidigm). Extensive clinical/serological evaluations were also performed. In vitro studies involving over/down-expression of splicing machinery components were developed.

Results: Infiltration of CD68+ expressing cells was confirmed in kidney biopsies and associated with parameters of kidney failure (C3/C4, chronic index), highlighting the key role of the myeloid compartment in lupus nephropathy. Gene expression profiling recognized 156 genes differentially expressed in SLE monocytes vs HDs, most of them associated with the IFN response. In parallel, the altered expression of 27 components of the splicing machinery (SM) was revealed in SLE-monocytes. Correlation studies demonstrated that the aberrant expression of SM components was linked to both, the altered IFN signature and the plasma inflammatory profile. This altered molecular profile was associated with disease activity, anti-dsDNA positivity and C3/C4 levels. Interestingly, SLE patients with renal disease displayed a simultaneous alteration of both, the IFN and the SM signatures in monocytes, along with an enlarged pro-inflammatory profile in plasma. Logistic regression models integrating the concomitant alteration of SM components and IFNs genes identified lupus nephritis patients with high accuracy. In vitro SLE-serum promoted in DS-monocytes a concomitant deregulation of both, the IFN signature and several SM components. Besides, the over/down-expression of selected SM components in SLE-monocytes reduced the release of inflammatory cytokines and their adhesion capacity.

Conclusion: 1) Monocytes from SLE patients with renal involvement exhibit a remarkable alteration of genes associated with the IFN response, further linked with the aberrant expression of several SM components. 2) Serum SLE promoted the dysregulation in monocytes of both, the IFN and spliceosome signatures, along with an active release of proinflammatory mediators. 3) The modulation of key SM components in monocytes from SLE patients reduce their pro-inflammatory status and migration capacity.

« Back to ACR Convergence 2021

ACR Meeting Abstracts - https://acrabstracts.org/abstract/kidney-disease-in-lupus-patients-is-linked-to-monocytes-aberrant-spliceosome-and-altered-expression-of-ifn-response-related-genes/