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

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