Evaluating the in vitro effects of selective and potent non-selective fibroblast growth factor receptor inhibition in human BL2 cells as potential therapeutic targets for multiple sclerosis

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vonAuLaureen-2025-11-18.pdf (10.06 MB)

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2025

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DOI:
https://doi.org/10.22029/jlupub-20738

Abstract

B lymphocytes play a key role in the pathogenesis of multiple sclerosis (MS). While B-cell-depleting therapies have demonstrated clinical efficacy, emerging therapeutic strategies focus on functional modulation of B cells to preserve overall immune homeostasis. In addition to B cells, molecular signaling pathways such as the B cell receptor pathway, targeted by Bruton’s tyrosine kinase inhibitor and fibroblast growth factor (FGF/FGFR) signaling, important for neurodegeneration and immune regulation in the central nervous system, have gained attention. Experimental autoimmune encephalomyelitis models showed that conditional deletion of FGFR1/2 in oligodendrocytes resulted in a milder disease course, reduced inflammation, and decreased myelin and axon degeneration. In demyelinating lesions, the number of immune cells was significantly reduced, indicating that FGF/FGFR signaling might play an important role in immune cell modulation. This study investigated the effects of pharmacological FGFR inhibition on BL2 cells. Selective FGFR inhibitors (AZD4547, infigratinib) and the multikinase inhibitor dovitinib were investigated for their effects on BL2 cell proliferation, cytotoxicity, receptor expression (FGFR1/2), intracellular signaling (pERK, pAkt), and cytokine production using WST-1 and LDH assays, immunofluorescence, western blot, and RT-PCR. Under in vitro conditions, FGFR inhibition did not affect BL2 cell proliferation or exerted cytotoxic effects. Dovitinib significantly reduced the surface expression of FGFR1, pERK activation, and the secretion of the pro inflammatory cytokines IL6 and IL12, both important in the pathophysiology of MS. In contrast, selective FGFR inhibitors had only minor effects. FGFR2 mRNA levels were reduced across all treatment groups, and protein levels remained unchanged, suggesting posttranscriptional regulation or the activation of compensatory feedback mechanisms. An increase in pAkt activity, particularly following infigratinib treatment, further indicates the activation of alternative signaling pathways in response to FGFR blockade. The enhanced efficacy of dovitinib might be due to its broader kinase inhibition profile, targeting not only FGFR but also additional tyrosine kinases. In summary, this study shows that the multikinase FGFR inhibitor dovitinib can modulate pro-inflammatory B cell activity without compromising cell viability, offering a promising strategy as a targeted immunomodulatory approach for MS therapy.

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