NOVEL molecular regulators of rheumatoid arthritis (RA) inflammation were presented as part of a plenary abstract session at the ACR Convergence 2024 in Washington, D.C. Using a custom CRISPR deletion screen, the study identified key genes that drive the pathogenic activation of synovial fibroblasts, paving the way for potential new therapeutic approaches.
RA, a chronic autoimmune disease, involves synovial fibroblasts adopting an inflammatory phenotype that accelerates joint damage. Identifying ways to modulate these fibroblasts has long been a challenge for researchers. To address this, the study developed an innovative CRISPR-based approach that screened 132 genes for their roles in fibroblast-mediated inflammation.
Researchers targeted genes informed by integrated RNA-sequencing analyses, highlighting those highly expressed in RA fibroblasts and relevant to inflammatory pathways. Stimulated fibroblasts were then assessed for changes in inflammatory cytokine production, gene transcription, and protein expression. Targeting NFIL3, a transcription factor implicated in juvenile idiopathic arthritis and arthritis severity in mouse models, resulted in strong enrichment of the inflammation gene signature and upregulation of matrix metalloproteases, suggestive of an invasive phenotype. Deletion of SIX1, another transcription factor known to promote cell proliferation and tumorigenesis, potently decreased secretion of several cytokines, which was validated in multiple RA cell lines.
These results underscore the potential of CRISPR screening as a tool for uncovering targets for RA drug development. The authors highlighted that these “hits” may offer promising avenues for future therapeutic intervention.
Reference: Mueller A et al. CRISPR Deletion Screen in Fibroblasts Identifies Novel Regulators of Inflammation. Abstract 2531. ACR Convergence 2024, November 16-19, 2024.
