SPATS2L is a positive feedback regulator of the type I interferon signaling pathway and plays a vital role in lupus

Abstract

Through genome-wide association studies (GWAS) and integrated expression quantitative trait locus (eQTL) analyses, numerous susceptibility genes (“eGenes”, whose expressions are significantly associated with common variants) associated with systemic lupus erythematosus (SLE) have been identified. Notably, a subset of these eGenes is correlated with disease activity. However, the precise mechanisms through which these genes contribute to the initiation and progression of the disease remain to be fully elucidated. In this investigation, we initially identify SPATS2L as an SLE eGene correlated with disease activity. eSignaling and transcriptomic analyses suggest its involvement in the type I interferon (IFN) pathway. We observe a significant increase in SPATS2L expression following type I IFN stimulation, and the expression levels are dependent on both the concentration and duration of stimulation. Furthermore, through dual-luciferase reporter assays, western blot analysis, and imaging flow cytometry, we confirm that SPATS2L positively modulates the type I IFN pathway, acting as a positive feedback regulator. Notably, siRNA-mediated intervention targeting SPATS2L, an interferon-inducible gene, in peripheral blood mononuclear cells (PBMCs) from patients with SLE reverses the activation of the interferon pathway. In conclusion, our research highlights the pivotal role of SPATS2L as a positive-feedback regulatory molecule within the type I IFN pathway. Our findings suggest that SPATS2L plays a critical role in the onset and progression of SLE and may serve as a promising target for disease activity assessment and intervention strategies.

1. Introduction

Systemic lupus erythematosus (SLE) is a typical chronic autoimmune disorder characterized by a notable genetic predisposition [1]. This condition manifests as multi-organ involvement, affecting diverse bodily systems, including the integumentary, musculoskeletal, renal, pulmonary, and cardiovascular systems. Despite extensive research endeavors, the exact etiology of lupus remains incompletely understood. Nonetheless, numerous investigations have revealed potential associations with genetic, environmental, and hormonal factors [2].

Genetic variations play a crucial role in both the etiology and pathogenesis of SLE [3–5]. In recent years, many studies, predominantly genome-wide association studies (GWAS), have made significant advancements in elucidating the underlying pathogenic mechanisms of SLE [6–12]. Through the analysis of large-scale genotype data, current investigations have identified numerous genetic variations linked to susceptibility to SLE. Notably, a considerable proportion of these variations are associated with the dysregulated expression of genes, such as IRF5, TYK2, and STAT4, within the interferon (IFN) pathway [13–16], underscoring the significant involvement of the IFN signaling network in the pathogenesis of SLE.

Previous studies have demonstrated that the majority of individuals with SLE exhibit dysregulated expression of IFN-stimulated genes (ISGs), commonly referred to as the “IFN signature” [17–19]. Consequently, elevated level of type I IFN in serum serves as a notable marker for SLE patients [20–22]. Excessive IFN stimulates the generation of autoantibodies and instigates the upregulation of genes associated with immune responses, including cytokines, chemokines, and other inflammatory mediators, thereby promoting inflammation and contributing to the progression of SLE [23–25]. The aberrant activation of type I IFN is a major pathogenic factor in SLE and plays a pivotal role in the initiation and progression of lupus. Consequently, targeting this pathway has emerged as a promising therapeutic approach for managing this disease. Currently, numerous therapeutic strategies targeting interferons or their receptors are extensively employed in the treatment of SLE. These include, an approved monoclonal antibody targeting the type I interferon receptor (IFNAR), as well as investigational therapeutics such as interferon alpha (IFN-α) kinoid, and those which specifically target IFN-α [26–31].