Assessing the translational relevance of specific molecular pathways in spontaneous lupus mouse models

Abstract

Background: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by loss of self-tolerance, causing inflammation and tissue damage in multiple organs. Although animal models have advanced our understanding of SLE's molecular basis, recent regulatory changes and longstanding concerns regarding reproducibility and translatability have renewed the need to critically evaluate how these models mirror human disease. Understanding pathway-level similarities and differences between mouse models and human disease is essential, given the marked clinical and molecular heterogeneity of SLE.

Methods: Four spontaneous SLE mouse models were studied: MRL ^lpr/lpr , NZB/W, BXSB.Yaa, and Tlr7.Tg6. Transcriptome sequencing from blood, spleen, and kidney; flow cytometry from the spleen; and cytokines and autoantibody measurement in plasma were performed at four time points. Similar molecular datasets from the human PRECISESADS SLE cohort were used for the integration.

Results: The study identified specific molecular pathways driving the phenotype in each mouse model and established a framework describing the dynamics of these phenotype-associated molecular signatures, thereby facilitating the selection of time points of interest for future mouse-oriented experimental designs. In addition, by comparing these pathways with those observed in human SLE, we identified the most similar ones and their relationship with disease activity, providing crucial insight into their translational relevance. Importantly, disease severity across models was linked to both the extent and timing of molecular dysregulations. As expected, MRL ^lpr/lpr showed the most aggressive phenotype with early immune activation and apoptosis dysregulation, while Tlr7.Tg6 presented late-onset signatures associated with interferon and inflammation. Shared molecular features with human SLE included interferon responses, T and B cell depletion, and neutrophil activation. Integration analysis revealed distinct, yet overlapping, immune pathways between models and species, with some signatures such as age-associated B cells and double-negative memory T cells being model-specific but potentially relevant to early disease processes.

Conclusions: These findings provide a valuable framework for future SLE research and reinforce the utility of mouse models for studying specific molecular pathways related to human SLE pathogenesis and heterogeneity. The integration of longitudinal mouse and human molecular information highlights the models that best recapitulate key aspects of human disease, offering guidance for the study of specific immunopathological mechanisms or therapeutic targets.

Keywords: autoantibodies; cytokines; flow cytometry; molecular integration; mouse models; systemic lupus erythematosus.