FL/FLT3 signaling enhances mechanical pain hypersensitivity through Interleukin-1 beta (IL-1β) in male mice

Sonrier, C.; Sar, C.; Melo, I.; Diouloufet, L.; Lucena-Silva, G. V.; Mallie, S.; Bertin, J.; Leyris, J.-P.; Ango, F.; Cunha, T. M.; Moha ou Maati, H.; Valmier, J.; Rivat, C.; Mechaly, I.

doi:10.1101/2025.04.09.648037

bioRxiv · 10.1101/2025.04.09.648037

FL/FLT3 signaling enhances mechanical pain hypersensitivity through Interleukin-1 beta (IL-1β) in male mice

Sonrier, C.·Sar, C.·Melo, I.·Diouloufet, L.·Lucena-Silva, G. V.·Mallie, S.·Bertin, J.·Leyris, J.-P.·Ango, F.·Cunha, T. M.·Moha ou Maati, H.·Valmier, J.·Rivat, C.·Mechaly, I.

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Abstract

Fms-like tyrosine kinase 3 (FLT3) plays a critical role in chronic pain through its ligand FL, a cytokine that triggers mechanical pain hypersensitivity. However, the underlying molecular mechanisms remain unclear. Here, we investigate the potential interplay between FL and IL-1{beta} a key cytokine in DRG neurons sensitization and mechanical hyperalgesia through both in vitro and in vivo approaches. ELISA assays reveal that intrathecal FL administration significantly increases IL-1{beta} protein levels in both the DRG and dorsal spinal cord of mice, beginning four hours post-injection. Using video microscopy and [Ca2+]i fluorescence imaging in primary DRG neuron cultures, we demonstrate that FL potentiation of TRPV1 receptor responses to capsaicin is partially mediated by IL-1{beta} signalling, as evidenced by a significant reduction in this potentiation in the presence of the IL-1 receptor antagonist, IL-1Ra. Furthermore, FLT3-driven acute mechanical pain hypersensitivity in vivo is reduced both by prior administration of IL-1Ra and in IL-1 receptor knockout mice. Importantly, IL-1{beta}-induced mechanical pain hypersensitivity remains independent of FLT3 signalling as shown in Flt3 knockout mice. Collectively our findings expand the understanding of neuro-immune interactions by demonstrating a potential functional link between FL/FLT3 and IL-1{beta}/IL-1R signalling in nociceptive processing. HighlightsCytokines are known to engage in complex interactions and regulate each other FL increases IL-1{beta} in DRG and DSC within 4h, but IL-1{beta} does not affect FL levels FL modulates capsaicin-induced Ca2+ influx via IL-1{beta}/IL-1R signalling in DRG neurons IL-1R inhibition delays or abolishes FL-induced mechanical hypersensitivity in vivo Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/648037v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@11cfa96org.highwire.dtl.DTLVardef@187ac2borg.highwire.dtl.DTLVardef@387234org.highwire.dtl.DTLVardef@1d1c058_HPS_FORMAT_FIGEXP M_FIG The timeline of the experimental design and the graphical abstract were created with BioRender.com C_FIG

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Sonrier, C., Sar, C., Melo, I., Diouloufet, L., Lucena-Silva, G. V., Mallie, S., Bertin, J., Leyris, J.-P., Ango, F., Cunha, T. M., Moha ou Maati, H., Valmier, J., Rivat, C., Mechaly, I.. 2025-04-15. FL/FLT3 signaling enhances mechanical pain hypersensitivity through Interleukin-1 beta (IL-1β) in male mice. https://doi.org/10.1101/2025.04.09.648037

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